Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Controlling the biodistribution and clearance of nanomedicines

Nature Reviews Bioengineering volume 2, pages 214–232 (2024)Cite this article

Subjects

Abstract

Nanomedicines improve drug bioavailability, the dose–response relationship, targeting ability, efficacy and safety compared to conventional freely administered drugs. Nonetheless, despite their success as carriers for SARS-CoV-2 vaccines, clinical use of nanomedicines is still limited, probably caused by mismatches between animal models and humans. In this Review, we propose that improving blood circulation, biodistribution and tissue accessibility could help improve the clinical translation of nanomedicines. Specifically, we emphasize control of the pharmacokinetics relevant to the administration route, therapeutic targets in tissues and cells, and the drug payloads. Furthermore, we analyse the clearance and distribution of nanomedicines in preclinical and clinical studies, highlighting the biological barriers determining their in vivo performance. Finally, we present engineering strategies, such as size tuning, active targeting for transcytosis, external stimuli and biological shifts, to overcome these barriers.

Key points

  • Nanomedicines can improve bioavailability, targeting ability, efficacy and safety compared to carrier-free drugs, although their clinical translation has been limited.

  • Understanding the mechanisms influencing blood circulation, biodistribution and tissue accessibility of nanomedicines can help overcome these limitations.

  • Investigating the interplay between the structure and function of nanomedicines and their biological interactions can help develop nanomedicines with improved delivery efficiency.

  • Bioengineering strategies can be used to optimize nanomedicine design, manipulate biological barriers and enhance tissue targeting to improve clinical efficacy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Theoretical postulate of targeted nanomedicines.
Fig. 2: Strategies for the modulation of pharmacokinetics through nanocarrier design and engineering of biological barriers.
Fig. 3: Analysis of preclinical and clinical parameters of clinically approved nanomedicines.

Similar content being viewed by others

References

  1. Fan, W., Yung, B., Huang, P. & Chen, X. Nanotechnology for multimodal synergistic cancer therapy. Chem. Rev. 117, 13566–13638 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Cabral, H., Miyata, K., Osada, K. & Kataoka, K. Block copolymer micelles in nanomedicine applications. Chem. Rev. 118, 6844–6892 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Kopecek, J. & Yang, J. Polymer nanomedicines. Adv. Drug Deliv. Rev. 156, 40–64 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    Article  CAS  PubMed  Google Scholar 

  5. Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic: an update post COVID-19 vaccines. Bioeng. Transl. Med. 6, e10246 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen, S. et al. Nanotechnology-based mRNA vaccines. Nat. Rev. Methods Primers 3, 63 (2023).

    Article  CAS  Google Scholar 

  7. Toy, R., Bauer, L., Hoimes, C., Ghaghada, K. B. & Karathanasis, E. Targeted nanotechnology for cancer imaging. Adv. Drug Deliv. Rev. 76, 79–97 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Mitchell, M. J., Jain, R. K. & Langer, R. Engineering and physical sciences in oncology: challenges and opportunities. Nat. Rev. Cancer 17, 659–675 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang, J. et al. Challenging the fundamental conjectures in nanoparticle drug delivery for chemotherapy treatment of solid cancers. Adv. Drug Deliv. Rev. 190, 114525 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Smedsrød, B. et al. Cell biology of liver endothelial and Kupffer cells. Gut 35, 1509–1516 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Shetty, S., Lalor, P. F. & Adams, D. H. Liver sinusoidal endothelial cells — gatekeepers of hepatic immunity. Nat. Rev. Gastroenterol. Hepatol. 15, 555–567 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mulder, W. J. M., Jaffer, F. A., Fayad, Z. A. & Nahrendorf, M. Imaging and nanomedicine in inflammatory atherosclerosis.Sci. Transl. Med. 6, 239sr1 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shi, J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Rubey, K. M. & Brenner, J. S. Nanomedicine to fight infectious disease. Adv. Drug Deliv. Rev. 179, 113996 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhou, J. et al. Biomaterials and nanomedicine for bone regeneration: progress and future prospects. Exploration 1, 20210011 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dawson, K. A. & Yan, Y. Current understanding of biological identity at the nanoscale and future prospects. Nat. Nanotechnol. 16, 229–242 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Allen, T. M. & Hansen, C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim. Biophys. Acta 1068, 133–141 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Nishiyama, N. et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res. 63, 8977–8983 (2003).

    CAS  PubMed  Google Scholar 

  19. Cabral, H., Nishiyama, N. & Kataoka, K. Optimization of (1,2-diamino-cyclohexane)platinum(II)-loaded polymeric micelles directed to improved tumor targeting and enhanced antitumor activity. J. Control. Release 121, 146–155 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Mochida, Y. et al. Bundled assembly of helical nanostructures in polymeric micelles loaded with platinum drugs enhancing therapeutic efficiency against pancreatic tumor. ACS Nano 8, 6724–6738 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Wen, P. et al. Stealth and pseudo-stealth nanocarriers. Adv. Drug Deliv. Rev. 198, 114895 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Li, M., Al-Jamal, K. T., Kostarelos, K. & Reineke, J. Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano 4, 6303–6317 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pattipeiluhu, R. et al. Anionic lipid nanoparticles preferentially deliver mRNA to the hepatic reticuloendothelial system. Adv. Mater. 34, e2201095 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Anraku, Y., Kishimura, A., Kobayashi, A., Oba, M. & Kataoka, K. Size-controlled long-circulating PICsome as a ruler to measure critical cut-off disposition size into normal and tumor tissues. Chem. Commun. 47, 6054–6056 (2011).

    Article  CAS  Google Scholar 

  26. Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).

    Article  ADS  PubMed  Google Scholar 

  27. He, C., Hu, Y., Yin, L., Tang, C. & Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31, 3657–3666 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Albanese, A., Tang, P. S. & Chan, W. C. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 14, 1–16 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Hirn, S. et al. Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur. J. Pharm. Biopharm. 77, 407–416 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Xiao, K. et al. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials 32, 3435–3446 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dirisala, A. et al. Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines. Sci. Adv. 6, eabb8133 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. Takahashi, S., Wada, N., Harada, K. & Nagata, M. Cationic charge-preferential IgG reabsorption in the renal proximal tubules. Kidney Int. 66, 1556–1560 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Jonge, M. J. et al. Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation. Eur. J. Cancer 46, 3016–3021 (2010).

    Article  PubMed  Google Scholar 

  35. Oe, Y. et al. Actively-targeted polyion complex micelles stabilized by cholesterol and disulfide cross-linking for systemic delivery of siRNA to solid tumors. Biomaterials 35, 7887–7895 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Li, J. et al. Ternary polyplex micelles with PEG shells and intermediate barrier to complexed DNA cores for efficient systemic gene delivery. J. Control. Release 209, 77–87 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Christie, R. J. et al. Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection. ACS Nano 6, 5174–5189 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Watanabe, S. et al. In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers. Nat. Commun. 10, 1894 (2019).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  39. Japan Registry of Clinical Trials. https://jrct.niph.go.jp/en-latest-detail/jRCT2031190181 (2020).

  40. Topper, J. N. & Gimbrone, M. A. Jr Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol. Med. Today 5, 40–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Takeda, K. M. et al. Effect of shear stress on structure and function of polyplex micelles from poly(ethylene glycol)-poly(l-lysine) block copolymers as systemic gene delivery carrier. Biomaterials 126, 31–38 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Carter, P. J. & Senter, P. D. Antibody-drug conjugates for cancer therapy. Cancer J. 14, 154–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Han, Y., Wen, P., Li, J. & Kataoka, K. Targeted nanomedicine in cisplatin-based cancer therapeutics. J. Control. Release 345, 709–720 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Sievers, E. L. & Senter, P. D. Antibody-drug conjugates in cancer therapy. Annu. Rev. Med. 64, 15–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT00003165 (2013).

  46. Vasey, P. A. et al. Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee. Clin. Cancer Res. 5, 83–94 (1999).

    CAS  PubMed  Google Scholar 

  47. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT01861496 (2022).

  48. Jakobsen, E. H. et al. Liposomal cisplatin response prediction in heavily pretreated breast cancer patients: a multigene biomarker in a prospective phase 2 study. J. Clin. Oncol. 36, e13077 (2018).

    Article  Google Scholar 

  49. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03168061 (2020).

  50. Chawla, S. P. et al. A phase 1b dose escalation trial of NC-6300 (nanoparticle epirubicin) in patients with advanced solid tumors or advanced, metastatic, or unresectable soft-tissue sarcoma. Clin. Cancer Res. 26, 4225–4232 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Kinoh, H. et al. Translational nanomedicine boosts anti-PD1 therapy to eradicate orthotopic PTEN-negative glioblastoma. ACS Nano 14, 10127–10140 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Li, J. & Kataoka, K. Chemo-physical strategies to advance the in vivo functionality of targeted nanomedicine: the next generation. J. Am. Chem. Soc. 143, 538–559 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Li, J. et al. Polymer prodrug-based nanoreactors activated by tumor acidity for orchestrated oxidation/chemotherapy. Nano Lett. 17, 6983–6990 (2017).

    Article  ADS  CAS  PubMed  Google Scholar 

  54. Li, J. et al. Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy. J. Control. Release 225, 64–74 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  55. Shibasaki, H. et al. Efficacy of pH-sensitive nanomedicines in tumors with different c-MYC expression depends on the intratumoral activation profile. ACS Nano 15, 5545–5559 (2021).

    Article  CAS  PubMed  Google Scholar 

  56. Suk, J. S., Xu, Q., Kim, N., Hanes, J. & Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28–51 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. Yamaoka, T., Tabata, Y. & Ikada, Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 83, 601–606 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Hatakeyama, H., Akita, H. & Harashima, H. The polyethyleneglycol dilemma: advantage and disadvantage of PEGylation of liposomes for systemic genes and nucleic acids delivery to tumors. Biol. Pharm. Bull. 36, 892–899 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Dams, E. T. et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J. Pharmacol. Exp. Ther. 292, 1071–1079 (2000).

    CAS  PubMed  Google Scholar 

  60. Sherman, M. R., Williams, L. D., Sobczyk, M. A., Michaels, S. J. & Saifer, M. G. Role of the methoxy group in immune responses to mPEG-protein conjugates. Bioconjugate Chem. 23, 485–499 (2012).

    Article  CAS  Google Scholar 

  61. Ishihara, T. et al. Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles. Pharm. Res. 26, 2270–2279 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Abu Lila, A. S., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J. Control. Release 172, 38–47 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Kierstead, P. H. et al. The effect of polymer backbone chemistry on the induction of the accelerated blood clearance in polymer modified liposomes. J. Control. Release 213, 1–9 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jeon, M., Lee, W. & Im, H. J. Unexpected accelerated blood clearance phenomenon in albumin coated liposome. J. Nucl. Med. 62, 1265 (2021).

    Google Scholar 

  65. Yang, Q. et al. Analysis of pre-existing IgG and IgM antibodies against polyethylene glycol (PEG) in the general population. Anal. Chem. 88, 11804–11812 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Saifer, M. G., Williams, L. D., Sobczyk, M. A., Michaels, S. J. & Sherman, M. R. Selectivity of binding of PEGs and PEG-like oligomers to anti-PEG antibodies induced by methoxyPEG-proteins. Mol. Immunol. 57, 236–246 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Shimizu, T. et al. Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response. Biol. Pharm. Bull. 35, 1336–1342 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Ishida, T., Ichihara, M., Wang, X. & Kiwada, H. Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes. J. Control. Release 115, 243–250 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Ichihara, M. et al. Anti-PEG IgM response against PEGylated liposomes in mice and rats. Pharmaceutics 3, 1–11 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Semple, S. C. et al. Immunogenicity and rapid blood clearance of liposomes containing polyethylene glycol-lipid conjugates and nucleic acid. J. Pharmacol. Exp. Ther. 312, 1020–1026 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Koide, H. et al. T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes. Int. J. Pharm. 392, 218–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Mima, Y., Hashimoto, Y., Shimizu, T., Kiwada, H. & Ishida, T. Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol. Pharm. 12, 2429–2435 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Koide, H. et al. Particle size-dependent triggering of accelerated blood clearance phenomenon. Int. J. Pharm. 362, 197–200 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Kaminskas, L. M., McLeod, V. M., Porter, C. J. & Boyd, B. J. Differences in colloidal structure of PEGylated nanomaterials dictate the likelihood of accelerated blood clearance. J. Pharm. Sci. 100, 5069–5077 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Koide, H. et al. Size-dependent induction of accelerated blood clearance phenomenon by repeated injections of polymeric micelles. Int. J. Pharm. 432, 75–79 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Grenier, P., Viana, I. M. O., Lima, E. M. & Bertrand, N. Anti-polyethylene glycol antibodies alter the protein corona deposited on nanoparticles and the physiological pathways regulating their fate in vivo. J. Control. Release 287, 121–131 (2018).

    Article  CAS  PubMed  Google Scholar 

  77. Shiraishi, K. et al. Exploring the relationship between anti-PEG IgM behaviors and PEGylated nanoparticles and its significance for accelerated blood clearance. J. Control. Release 234, 59–67 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. McSweeney, M. D. et al. Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG. J. Control. Release 311-312, 138–146 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ju, Y. et al. Anti-PEG antibodies boosted in humans by SARS-CoV-2 lipid nanoparticle mRNA vaccine. ACS Nano 16, 11769–11780 (2022).

    Article  CAS  PubMed  Google Scholar 

  80. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02240238 (2020).

  81. Tockary, T. A. et al. Tethered PEG crowdedness determining shape and blood circulation profile of polyplex micelle gene carriers. Macromolecules 46, 6585–6592 (2013).

    Article  ADS  CAS  Google Scholar 

  82. FDA. Moderna COVID-19 Vaccine EUA Fact Sheet for Recipients and Caregivers 08312022 https://www.fda.gov/media/144638/download (2020).

  83. Pfizer Inc. Fact Sheet for Healthcare Providers Administering Vaccine, Revised https://labeling.pfizer.com/ShowLabeling.aspx?id=14471 (2020).

  84. Ju, Y. et al. Impact of anti-PEG antibodies induced by SARS-CoV-2 mRNA vaccines. Nat. Rev. Immunol. 23, 135–136 (2023).

    Article  CAS  PubMed  Google Scholar 

  85. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020. Morb. Mortal. Wkly. Rep.70, 46–51 (2021).

  86. Carreno, J. M. et al. mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations. Vaccine 40, 6114–6124 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Suzuki, T. et al. PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: faster PEG shedding attenuates anti-PEG IgM production. Int. J. Pharm. 588, 119792 (2020).

    Article  CAS  PubMed  Google Scholar 

  88. FDA. FDA Drug Safety Communication: FDA Strengthens Warnings and Changes Prescribing Instructions to Decrease the Risk of Serious Allergic Reactions with Anemia Drug Feraheme (Ferumoxytol) https://www.fda.gov/Drugs/DrugSafety/ucm440138.htm (2015).

  89. Chuang, H. C. et al. Allergenicity and toxicology of inhaled silver nanoparticles in allergen-provocation mice models. Int. J. Nanomed. 8, 4495–4506 (2013).

    Article  Google Scholar 

  90. de Haar, C., Hassing, I., Bol, M., Bleumink, R. & Pieters, R. Ultrafine but not fine particulate matter causes airway inflammation and allergic airway sensitization to co-administered antigen in mice. Clin. Exp. Allergy 36, 1469–1479 (2006).

    Article  PubMed  Google Scholar 

  91. Ilves, M. et al. Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model. Part. Fibre Toxicol. 11, 38 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Szebeni, J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol. Immunol. 61, 163–173 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Belime, A. et al. Recognition protein C1q of innate immunity agglutinates nanodiamonds without activating complement. Nanomedicine 18, 292–302 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Wibroe, P. P. et al. Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes. Nat. Nanotechnol. 12, 589–594 (2017).

    Article  ADS  CAS  PubMed  Google Scholar 

  95. Caceres, M. C. et al. The importance of early identification of infusion-related reactions to monoclonal antibodies. Ther. Clin. Risk Manag. 15, 965–977 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Szebeni, J., Simberg, D., González-Fernández, Á., Barenholz, Y. & Dobrovolskaia, M. A. Roadmap and strategy for overcoming infusion reactions to nanomedicines. Nat. Nanotechnol. 13, 1100–1108 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bertrand, N. et al. Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics. Nat. Commun. 8, 777 (2017).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  98. Berrecoso, G., Crecente-Campo, J. & Alonso, M. J. Unveiling the pitfalls of the protein corona of polymeric drug nanocarriers. Drug Deliv. Transl. Res. 10, 730–750 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Caracciolo, G. et al. The liposome-protein corona in mice and humans and its implications for in vivo delivery. J. Mater. Chem. B 2, 7419–7428 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Lundqvist, M. et al. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl Acad. Sci. USA 105, 14265–14270 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jung, S. Y. et al. The Vroman effect: a molecular level description of fibrinogen displacement. J. Am. Chem. Soc. 125, 12782–12786 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Partikel, K., Korte, R., Mulac, D., Humpf, H. U. & Langer, K. Serum type and concentration both affect the protein-corona composition of PLGA nanoparticles. Beilstein J. Nanotechnol. 10, 1002–1015 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Barran-Berdon, A. L. et al. Time evolution of nanoparticle-protein corona in human plasma: relevance for targeted drug delivery. Langmuir 29, 6485–6494 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Hadjidemetriou, M. et al. In vivo biomolecule corona around blood-circulating, clinically used and antibody-targeted lipid bilayer nanoscale vesicles. ACS Nano 9, 8142–8156 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Hajipour, M. J. et al. Personalized disease-specific protein corona influences the therapeutic impact of graphene oxide. Nanoscale 7, 8978–8994 (2015).

    Article  ADS  CAS  PubMed  Google Scholar 

  106. Chen, J. et al. In situ cancer vaccination using lipidoid nanoparticles. Sci. Adv. 7, eabf12 (2021).

    Google Scholar 

  107. Zhang, Y. et al. Multifunctional nanoparticle potentiates the in situ vaccination effect of radiation therapy and enhances response to immune checkpoint blockade. Nat. Commun. 13, 4948 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  108. Alberg, I. et al. Polymeric nanoparticles with neglectable protein corona. Small 16, e1907574 (2020).

    Article  PubMed  Google Scholar 

  109. Takeda, K. M. et al. Poly(ethylene glycol) crowding as critical factor to determine pDNA packaging scheme into polyplex micelles for enhanced gene expression. Biomacromolecules 18, 36–43 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Tockary, T. A. et al. Rod-to-globule transition of pDNA/PEG-poly(l-lysine) polyplex micelles induced by a collapsed balance between DNA rigidity and PEG crowdedness. Small 12, 1193–1200 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Vincent, M. P. et al. Surface chemistry-mediated modulation of adsorbed albumin folding state specifies nanocarrier clearance by distinct macrophage subsets. Nat. Commun. 12, 648 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen, D., Ganesh, S., Wang, W. & Amiji, M. Protein corona-enabled systemic delivery and targeting of nanoparticles. AAPS J. 22, 83 (2020).

    Article  CAS  PubMed  Google Scholar 

  113. Schottler, S., Landfester, K. & Mailander, V. Controlling the stealth effect of nanocarriers through understanding the protein corona. Angew. Chem. Int. Ed. Engl. 55, 8806–8815 (2016).

    Article  PubMed  Google Scholar 

  114. Hadjidemetriou, M., Al-Ahmady, Z., Buggio, M., Swift, J. & Kostarelos, K. A novel scavenging tool for cancer biomarker discovery based on the blood-circulating nanoparticle protein corona. Biomaterials 188, 118–129 (2019).

    Article  CAS  PubMed  Google Scholar 

  115. Xu, W. et al. Changes in target ability of nanoparticles due to protein corona composition and disease state. Asian J. Pharm. Sci. 17, 401–411 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Hadjidemetriou, M. et al. The human in vivo biomolecule corona onto PEGylated liposomes: a proof‐of‐concept clinical study. Adv. Mater. 31, e1803335 (2019).

    Article  PubMed  Google Scholar 

  117. Di Domenico, M. et al. Nanoparticle-biomolecular corona: a new approach for the early detection of non-small-cell lung cancer. J. Cell Physiol. 234, 9378–9386 (2019).

    Article  PubMed  Google Scholar 

  118. Kobos, L. M. et al. An integrative proteomic/lipidomic analysis of the gold nanoparticle biocorona in healthy and obese conditions. Appl. Vitro Toxicol. 5, 150–166 (2019).

    Article  CAS  Google Scholar 

  119. Colapicchioni, V. et al. Personalized liposome-protein corona in the blood of breast, gastric and pancreatic cancer patients. Int. J. Biochem. Cell Biol. 75, 180–187 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Chu, Y. et al. Deciphering protein corona by scFv-based affinity chromatography. Nano Lett. 21, 2124–2131 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  121. Pattipeiluhu, R. et al. Unbiased identification of the liposome protein corona using photoaffinity-based chemoproteomics. ACS Cent. Sci. 6, 535–545 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986). This article lays a foundation for designing cancer nanomedicines for targeted delivery based on the EPR effect.

    CAS  PubMed  Google Scholar 

  123. Hansen, A. E. et al. Positron emission tomography based elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano 9, 6985–6995 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Lee, H. et al. 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin. Cancer Res. 23, 4190–4202 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Fang, J., Nakamura, H. & Maeda, H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 63, 136–151 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Dvorak, H. F., Brown, L. F., Detmar, M. & Dvorak, A. M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029–1039 (1995). This study reports the discovery of a vesicular transport across tumour vasculature in angiogenesis, relevant to inflammation and cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Feng, D. et al. Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation 6, 23–44 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Roberts, W. G. & Palade, G. E. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res. 57, 765–772 (1997).

    CAS  PubMed  Google Scholar 

  129. Esser, S. et al. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J. Cell Biol. 140, 947–959 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Roberts, W. G. & Palade, G. E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Sci. 108, 2369–2379 (1995).

    Article  CAS  PubMed  Google Scholar 

  131. Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305 (1986).

    Article  CAS  PubMed  Google Scholar 

  132. Yuan, F. et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55, 3752–3756 (1995).

    CAS  PubMed  Google Scholar 

  133. Matsumoto, Y. et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat. Nanotechnol. 11, 533–538 (2016). This article reports the fast dynamic phenomena of paracellular transport during the EPR effect.

    Article  ADS  CAS  PubMed  Google Scholar 

  134. Igarashi, K. et al. Vascular bursts act as a versatile tumor vessel permeation route for blood-borne particles and cells. Small 17, e2103751 (2021).

    Article  PubMed  Google Scholar 

  135. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Nia, H. T. et al. Solid stress and elastic energy as measures of tumour mechanopathology. Nat. Biomed. Eng. 1, 0004 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Kalli, M. & Stylianopoulos, T. Defining the role of solid stress and matrix stiffness in cancer cell proliferation and metastasis. Front. Oncol. 8, 55 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Tanaka, H. Y. & Kano, M. R. Stromal barriers to nanomedicine penetration in the pancreatic tumor microenvironment. Cancer Sci. 109, 2085–2092 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ding, Y. et al. Investigating the EPR effect of nanomedicines in human renal tumors via ex vivo perfusion strategy. Nano Today 35, 100970 (2020).

    Article  CAS  Google Scholar 

  142. Miedema, I. H. C. et al. PET-CT imaging of polymeric nanoparticle tumor accumulation in patients. Adv. Mater. 34, e2201043 (2022).

    Article  PubMed  Google Scholar 

  143. Ramanathan, R. K. et al. Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: a pilot study. Clin. Cancer Res. 23, 3638–3648 (2017). This work reports that the EPR effect can be observed in patients but with substantial heterogeneity.

    Article  CAS  PubMed  Google Scholar 

  144. Nichols, J. W. & Bae, Y. H. EPR: evidence and fallacy. J. Control. Release 190, 451–464 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotechnol. 6, 815–823 (2011). This article indicates that size is a critical factor when designing nanomedicines for targeted delivery.

    Article  ADS  CAS  PubMed  Google Scholar 

  146. Tang, L. et al. Investigating the optimal size of anticancer nanomedicine. Proc. Natl Acad. Sci. USA 111, 15344–15349 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wang, H. X. et al. Surface charge critically affects tumor penetration and therapeutic efficacy of cancer nanomedicines. Nano Today 11, 133–144 (2016).

    Article  CAS  Google Scholar 

  148. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  ADS  CAS  Google Scholar 

  149. McNeil, S. Evaluation of nanomedicines: stick to the basics. Nat. Rev. Mater. 1, 16073 (2016).

    Article  ADS  Google Scholar 

  150. Price, L. S. L., Stern, S. T., Deal, A. M., Kabanov, A. V. & Zamboni, W. C. A reanalysis of nanoparticle tumor delivery using classical pharmacokinetic metrics. Sci. Adv. 6, eaay9249 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  151. Lammers, T. & Ferrari, M. The success of nanomedicine. Nano Today 31, 100853 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ricard, N., Bailly, S., Guignabert, C. & Simons, M. The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy. Nat. Rev. Cardiol. 18, 565–580 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wang, G. et al. Ultrasonic cavitation‐assisted and acid‐activated transcytosis of liposomes for universal active tumor penetration. Adv. Funct. Mater. 31, 2102786 (2021).

    Article  CAS  Google Scholar 

  154. Zhou, Q. et al. Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy. Nat. Nanotechnol. 14, 799–809 (2019).

    Article  CAS  PubMed  Google Scholar 

  155. Pluen, A., Netti, P. A., Jain, R. K. & Berk, D. A. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys. J. 77, 542–552 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Baxter, L. T. & Jain, R. K. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc. Res. 37, 77–104 (1989).

    Article  CAS  PubMed  Google Scholar 

  157. Netti, P. A., Baxter, L. T., Boucher, Y., Skalak, R. & Jain, R. K. Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery. Cancer Res. 55, 5451–5458 (1995).

    CAS  PubMed  Google Scholar 

  158. Baluk, P., Morikawa, S., Haskell, A., Mancuso, M. & McDonald, D. M. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 163, 1801–1815 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Cao, Y. et al. Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma. Cancer 119, 313–324 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Li, H., Fan, X. & Houghton, J. Tumor microenvironment: the role of the tumor stroma in cancer. J. Cell. Biochem. 101, 805–815 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Yokoi, K. et al. Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. Cancer Res. 74, 4239–4246 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jain, R. K. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6, 559–593 (1987).

    Article  CAS  PubMed  Google Scholar 

  163. Li, J. et al. Endogenous stimuli-sensitive multistage polymeric micelleplex anticancer drug delivery system for efficient tumor penetration and cellular internalization. Adv. Healthc. Mater. 4, 2206–2219 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Qiu, N. et al. Esterase-activated charge-reversal polymer for fibroblast-exempt cancer gene therapy. Adv. Mater. 28, 10613–10622 (2016).

    Article  CAS  PubMed  Google Scholar 

  165. Li, J. et al. Light-triggered clustered vesicles with self-supplied oxygen and tissue penetrability for photodynamic therapy against hypoxic tumor. Adv. Funct. Mater. 27, 1702108 (2017).

    Article  Google Scholar 

  166. He, Y. et al. A combinational chemo-immune therapy using an enzyme-sensitive nanoplatform for dual-drug delivery to specific sites by cascade targeting. Sci. Adv. 7, eaba0776 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  167. Awaad, A. et al. Changeable net charge on nanoparticles facilitates intratumor accumulation and penetration. J. Control. Release 346, 392–404 (2022).

    Article  CAS  PubMed  Google Scholar 

  168. Miura, Y. et al. Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier. ACS Nano 7, 8583–8592 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Suzuki, K. et al. Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors. J. Control. Release 301, 28–41 (2019).

    Article  CAS  PubMed  Google Scholar 

  170. Yang, T. et al. Conjugation of glucosylated polymer chains to checkpoint blockade antibodies augments their efficacy and specificity for glioblastoma. Nat. Biomed. Eng. 5, 1274–1287 (2021).

    Article  CAS  PubMed  Google Scholar 

  171. Miyazaki, T. et al. A hoechst reporter enables visualization of drug engagement in vitro and in vivo: toward safe and effective nanodrug delivery. ACS Nano 16, 12290–12304 (2022).

    Article  CAS  PubMed  Google Scholar 

  172. Ruoslahti, E. Tumor penetrating peptides for improved drug delivery. Adv. Drug Deliv. Rev. 110-111, 3–12 (2017).

    Article  CAS  PubMed  Google Scholar 

  173. Sivaram, A. J., Wardiana, A., Howard, C. B., Mahler, S. M. & Thurecht, K. J. Recent advances in the generation of antibody-nanomaterial conjugates. Adv. Healthc. Mater. 7, 1700607 (2018).

    Article  Google Scholar 

  174. Richards, D. A., Maruani, A. & Chudasama, V. Antibody fragments as nanoparticle targeting ligands: a step in the right direction. Chem. Sci. 8, 63–77 (2017).

    Article  CAS  PubMed  Google Scholar 

  175. Reuter, K. G. et al. Targeted PRINT hydrogels: the role of nanoparticle size and ligand density on cell association, biodistribution, and tumor accumulation. Nano Lett. 15, 6371–6378 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ansell, S. M., Tardi, P. G. & Buchkowsky, S. S. 3-(2-Pyridyldithio) propionic acid hydrazide as a cross-linker in the formation of liposome−antibody conjugates. Bioconjug. Chem. 7, 490–496 (1996).

    Article  CAS  PubMed  Google Scholar 

  177. Rodriguez, P. L. et al. Minimal “self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339, 971–975 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  178. Naito, M. et al. Size-tunable PEG-grafted copolymers as a polymeric nanoruler for passive targeting muscle tissues. J. Control. Release 347, 607–614 (2022).

    Article  CAS  PubMed  Google Scholar 

  179. Levick, J. R. & Smaje, L. H. An analysis of the permeability of a fenestra. Microvasc. Res. 33, 233–256 (1987).

    Article  CAS  PubMed  Google Scholar 

  180. Gonzalez-Carter, D. et al. Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium. Proc. Natl Acad. Sci. USA 117, 19141–19150 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  181. Anraku, Y. et al. Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain. Nat. Commun. 8, 1001 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  182. Rafiyath, S. M. et al. Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis. Exp. Hematol. Oncol. 1, 10 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. FDA. Taxol (Paclitaxel) Injection Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf (2011).

  184. FDA. Abraxane (Paclitaxel) Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf (2020).

  185. Mukai, H. et al. Phase I study of NK105, a nanomicellar paclitaxel formulation, administered on a weekly schedule in patients with solid tumors. Invest. New Drugs 34, 750–759 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. FDA. Docetaxel Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/201525s002lbl.pdf (2012).

  187. Von Hoff, D. D. et al. Phase I study of PSMA-targeted docetaxel-containing nanoparticle BIND-014 in patients with advanced solid tumors. Clin. Cancer Res. 22, 3157–3163 (2016).

    Article  Google Scholar 

  188. Atrafi, F. et al. A phase I dose-finding and pharmacokinetics study of CPC634 (nanoparticle entrapped docetaxel) in patients with advanced solid tumors. J. Clin. Oncol. 37, 3026 (2019).

    Article  Google Scholar 

  189. Liu, J. et al. Nanoscale-coordination-polymer-shelled manganese dioxide composite nanoparticles: a multistage redox/pH/H2O2-responsive cancer theranostic nanoplatform.Adv. Funct. Mater. 27, 1605926 (2017).

    Article  Google Scholar 

  190. Gao, S. et al. Selenium-containing nanoparticles combine the NK cells mediated immunotherapy with radiotherapy and chemotherapy. Adv. Mater. 32, e1907568 (2020).

    Article  PubMed  Google Scholar 

  191. Kinoh, H. et al. Nanomedicines eradicating cancer stem-like cells in vivo by pH-triggered intracellular cooperative action of loaded drugs. ACS Nano 10, 5643–5655 (2016).

    Article  CAS  PubMed  Google Scholar 

  192. Qin, S. Y., Cheng, Y. J., Lei, Q., Zhang, A. Q. & Zhang, X. Z. Combinational strategy for high-performance cancer chemotherapy. Biomaterials 171, 178–197 (2018).

    Article  CAS  PubMed  Google Scholar 

  193. Li, J. et al. Enzymatically transformable polymersome-based nanotherapeutics to eliminate minimal relapsable cancer. Adv. Mater. 33, 2105254 (2021).

    Article  CAS  Google Scholar 

  194. Rios-Doria, J. et al. Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia 17, 661–670 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Zhou, F. et al. Overcoming immune resistance by sequential prodrug nanovesicles for promoting chemoimmunotherapy of cancer. Nano Today 36, 101025 (2021).

    Article  CAS  Google Scholar 

  196. Islam, M. A. et al. Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. Nat. Biomed. Eng. 2, 850–864 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Cheng, K. et al. Synergistically enhancing the therapeutic effect of radiation therapy with radiation activatable and reactive oxygen species-releasing nanostructures. ACS Nano 12, 4946–4958 (2018).

    Article  CAS  PubMed  Google Scholar 

  198. Krauss, A. C. et al. FDA approval summary: (daunorubicin and cytarabine) liposome for injection for the treatment of adults with high-risk acute myeloid leukemia. Clin. Cancer Res. 25, 2685–2690 (2019).

    Article  CAS  PubMed  Google Scholar 

  199. Doncheva, N. T. et al. Human pathways in animal models: possibilities and limitations. Nucleic Acids Res. 49, 1859–1871 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Eliasof, S. et al. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proc. Natl Acad. Sci. USA 110, 15127–15132 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  201. Zuckerman, J. E. et al. Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA. Proc. Natl Acad. Sci. USA 111, 11449–11454 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  202. Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med. 4, 128ra39 (2012).

    Article  PubMed  Google Scholar 

  203. Oakley, R. & Tharakan, B. Vascular hyperpermeability and aging. Aging Dis. 5, 114–125 (2014).

    PubMed  PubMed Central  Google Scholar 

  204. Claesson-Welsh, L., Dejana, E. & McDonald, D. M. Permeability of the endothelial barrier: identifying and reconciling controversies. Trends Mol. Med. 27, 314–331 (2021).

    Article  CAS  PubMed  Google Scholar 

  205. Ioannidou, A., Fisher, R. M. & Hagberg, C. E. The multifaceted roles of the adipose tissue vasculature. Obes. Rev. 23, e13403 (2022).

    Article  PubMed  Google Scholar 

  206. Biozzi, G., Benacerraf, B. & Halpern, B. N. Quantitative study of the granulopectic activity of the reticulo-endothelial system. II. A study of the kinetics of the R. E. S. in relation to the dose of carbon injected; relationship between the weight of the organs and their activity. Br. J. Exp. Pathol. 34, 441–457 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Patel, K. R., Li, M. P. & Baldeschwieler, J. D. Suppression of liver uptake of liposomes by dextran sulfate 500. Proc. Natl Acad. Sci. USA 80, 6518–6522 (1983).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  208. Proffitt, R. T. et al. Liposomal blockade of the reticuloendothelial system: improved tumor imaging with small unilamellar vesicles. Science 220, 502–505 (1983).

    Article  ADS  CAS  PubMed  Google Scholar 

  209. Liu, D., Mori, A. & Huang, L. Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochim. Biophys. Acta 1104, 95–101 (1992).

    Article  CAS  PubMed  Google Scholar 

  210. Hwang, K. J. et al. Uptake of small liposomes by non-reticuloendothelial tissues. Biochim. Biophys. Acta 901, 88–96 (1987).

    Article  CAS  PubMed  Google Scholar 

  211. Oja, C. D., Semple, S. C., Chonn, A. & Cullis, P. R. Influence of dose on liposome clearance: critical role of blood proteins. Biochim. Biophys. Acta 1281, 31–37 (1996).

    Article  PubMed  Google Scholar 

  212. Diagaradjane, P., Deorukhkar, A., Gelovani, J. G., Maru, D. M. & Krishnan, S. Gadolinium chloride augments tumor-specific imaging of targeted quantum dots in vivo. ACS Nano 4, 4131–4141 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Wolfram, J. et al. A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery. Sci. Rep. 7, 13738 (2017).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  214. Abdollah, M. R. A. et al. Fucoidan prolongs the circulation time of dextran-coated iron oxide nanoparticles. ACS Nano 12, 1156–1169 (2018).

    Article  CAS  PubMed  Google Scholar 

  215. Abdollah, M. R. et al. Prolonging the circulatory retention of SPIONs using dextran sulfate: in vivo tracking achieved by functionalisation with near-infrared dyes. Faraday Discuss. 175, 41–58 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  216. Sun, X. et al. Improved tumor uptake by optimizing liposome based RES blockade strategy. Theranostics 7, 319–328 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Nikitin, M. P. et al. Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes. Nat. Biomed. Eng. 4, 717–731 (2020).

    Article  CAS  PubMed  Google Scholar 

  218. Gabizon, A. et al. An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother. Pharmacol. 61, 695–702 (2008).

    Article  CAS  PubMed  Google Scholar 

  219. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  220. Chen, Y., McAndrews, K. M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18, 792–804 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Amersfoort, J., Eelen, G. & Carmeliet, P. Immunomodulation by endothelial cells — partnering up with the immune system? Nat. Rev. Immunol. 22, 576–588 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. 19, 402–421 (2022).

    Article  PubMed  Google Scholar 

  223. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  224. Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  225. Chauhan, V. P. et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc. Natl Acad. Sci. USA 116, 10674–10680 (2019).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  226. Liu, J. et al. Nanoprobe-based magnetic resonance imaging of hypoxia predicts responses to radiotherapy, immunotherapy, and sensitizing treatments in pancreatic tumors. ACS Nano 15, 13526–13538 (2021).

    Article  CAS  PubMed  Google Scholar 

  227. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004).

    Article  CAS  PubMed  Google Scholar 

  228. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

    CAS  PubMed  Google Scholar 

  229. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10, 145–147 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT00254943 (2013).

  231. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT00662506 (2023).

  232. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Sorensen, A. G. et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res. 72, 402–407 (2012).

    Article  CAS  PubMed  Google Scholar 

  234. Stylianopoulos, T. et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc. Natl Acad. Sci. USA 109, 15101–15108 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  235. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    Article  CAS  PubMed  Google Scholar 

  237. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  238. Martin, J. D. et al. Dexamethasone increases cisplatin-loaded nanocarrier delivery and efficacy in metastatic breast cancer by normalizing the tumor microenvironment. ACS Nano 13, 6396–6408 (2019).

    Article  CAS  PubMed  Google Scholar 

  239. Fujiwara, A. et al. Effects of pirfenidone targeting the tumor microenvironment and tumor-stroma interaction as a novel treatment for non-small cell lung cancer. Sci. Rep. 10, 10900 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  240. Papageorgis, P. et al. Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner. Sci. Rep. 7, 46140 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  241. Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

    Article  ADS  PubMed  Google Scholar 

  242. Zhao, Y. et al. Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc. Natl Acad. Sci. USA 116, 2210–2219 (2019).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  243. Panagi, M. et al. TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity. Theranostics 10, 1910–1922 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT01821729 (2020).

  245. Murphy, J. E. et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 5, 1020–1027 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Panagi, M. et al. Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models. Nat. Commun. 13, 7165 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  247. Li, X., Lovell, J. F., Yoon, J. & Chen, X. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol. 17, 657–674 (2020).

    Article  PubMed  Google Scholar 

  248. Gunaydin, G., Gedik, M. E. & Ayan, S. Photodynamic therapy for the treatment and diagnosis of cancer — a review of the current clinical status. Front. Chem. 9, 686303 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Fingar, V. H. Vascular effects of photodynamic therapy. J. Clin. Laser Med. Surg. 14, 323–328 (1996).

    Article  CAS  PubMed  Google Scholar 

  250. Debefve, E. et al. Photodynamic therapy induces selective extravasation of macromolecules: insights using intravital microscopy. J. Photochem. Photobiol. B 98, 69–76 (2010).

    Article  CAS  PubMed  Google Scholar 

  251. Overchuk, M. et al. Subtherapeutic photodynamic treatment facilitates tumor nanomedicine delivery and overcomes desmoplasia. Nano Lett. 21, 344–352 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  252. Castano, A. P., Mroz, P. & Hamblin, M. R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 6, 535–545 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Abdel Fadeel, D. A., Kamel, R. & Fadel, M. PEGylated lipid nanocarrier for enhancing photodynamic therapy of skin carcinoma using curcumin: in-vitro/in-vivo studies and histopathological examination. Sci. Rep. 10, 10435 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  254. Lee, E. H., Lim, S. J. & Lee, M. K. Chitosan-coated liposomes to stabilize and enhance transdermal delivery of indocyanine green for photodynamic therapy of melanoma. Carbohydr. Polym. 224, 115143 (2019).

    Article  CAS  PubMed  Google Scholar 

  255. Miyazaki, K. et al. A novel photodynamic therapy for bladder cancer in an orthotopic rat model using a polymeric micelle encapsulating dendrimer-based phthalocyanine. Cancer Res. 68, 5614 (2008).

    Google Scholar 

  256. He, H. et al. Photoconversion-tunable fluorophore vesicles for wavelength-dependent photoinduced cancer therapy. Adv. Mater. 29, 1606690 (2017).

    Article  Google Scholar 

  257. Liu, J. et al. Tumor hypoxia-activated combinatorial nanomedicine triggers systemic antitumor immunity to effectively eradicate advanced breast cancer. Biomaterials 273, 120847 (2021).

    Article  CAS  PubMed  Google Scholar 

  258. Kadota, T. et al. A phase Ib study of near infrared photoimmunotherapy (NIR-PIT) using ASP-1929 in combination with nivolumab and for patients with advanced gastric or esophageal cancer (GE-PIT study, EPOC1901). J. Clin. Oncol. 38, TPS457 (2020).

    Article  Google Scholar 

  259. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03769506 (2023).

  260. Luo, Z. et al. Tumor-targeted hybrid protein oxygen carrier to simultaneously enhance hypoxia-dampened chemotherapy and photodynamic therapy at a single dose. Theranostics 8, 3584–3596 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Belcher, D. A., Lucas, A., Cabrales, P. & Palmer, A. F. Polymerized human hemoglobin facilitated modulation of tumor oxygenation is dependent on tumor oxygenation status and oxygen affinity of the hemoglobin-based oxygen carrier. Sci. Rep. 10, 11372 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Fan, X. et al. Oxygen self-supplied enzyme nanogels for tumor targeting with amplified synergistic starvation and photodynamic therapy. Acta Biomater. 142, 274–283 (2022).

    Article  CAS  PubMed  Google Scholar 

  263. Qiao, Y. et al. Engineered algae: a novel oxygen-generating system for effective treatment of hypoxic cancer. Sci. Adv. 6, eaba5996 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  264. Dings, R. P. et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin. Cancer Res. 13, 3395–3402 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  265. Znati, C. A. et al. Effect of radiation on interstitial fluid pressure and oxygenation in a human tumor xenograft. Cancer Res. 56, 964–968 (1996).

    CAS  PubMed  Google Scholar 

  266. Barker, H. E., Paget, J. T., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Debbage, P. L. et al. Vascular permeability and hyperpermeability in a murine adenocarcinoma after fractionated radiotherapy: an ultrastructural tracer study. Histochem. Cell Biol. 114, 259–275 (2000).

    Article  CAS  PubMed  Google Scholar 

  268. Hansen, A. E. et al. Liposome accumulation in irradiated tumors display important tumor and dose dependent differences. Nanomedicine 14, 27–34 (2018).

    Article  CAS  PubMed  Google Scholar 

  269. Price, L. S. L. et al. Minibeam radiation therapy enhanced tumor delivery of PEGylated liposomal doxorubicin in a triple-negative breast cancer mouse model. Ther. Adv. Med. Oncol. 13, 17588359211053700 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl. Med. 9, eaal0225 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  271. Koukourakis, M. I. et al. High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas–rationale for combination with radiotherapy. Acta Oncol. 39, 207–211 (2000).

    Article  CAS  PubMed  Google Scholar 

  272. Kouloulias, V. E. et al. Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial. Clin. Cancer Res. 8, 374–382 (2002).

    CAS  PubMed  Google Scholar 

  273. Koukourakis, M. I. et al. Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer. J. Clin. Oncol. 17, 3512–3521 (1999).

    Article  CAS  PubMed  Google Scholar 

  274. Panteliadou, M. et al. Concurrent administration of liposomal doxorubicin improves the survival of patients with invasive bladder cancer undergoing hypofractionated accelerated radiotherapy (HypoARC). Med. Oncol. 28, 1356–1362 (2011).

    Article  CAS  PubMed  Google Scholar 

  275. Hallahan, D. E. et al. Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature. J. Control. Release 74, 183–191 (2001).

    Article  CAS  PubMed  Google Scholar 

  276. Kamkaew, A., Chen, F., Zhan, Y., Majewski, R. L. & Cai, W. Scintillating nanoparticles as energy mediators for enhanced photodynamic therapy. ACS Nano 10, 3918–3935 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Freeman, M. W., Arrott, A. & Watson, J. H. L. Magnetism in medicine. J. Appl. Phys. 31, S404–S405 (1960).

    Article  ADS  Google Scholar 

  278. Lübbe, A. S. et al. Clinical experiences with magnetic drug targeting: a phase I study with 4′-epidoxorubicin in 14 patients with advanced solid tumors. Cancer Res. 56, 4686–4693 (1996).

    PubMed  Google Scholar 

  279. Wilson, M. W. et al. Hepatocellular carcinoma: regional therapy with a magnetic targeted carrier bound to doxorubicin in a dual MR imaging/conventional angiography suite — initial experience with four patients. Radiology 230, 287–293 (2004).

    Article  PubMed  Google Scholar 

  280. Polyak, B. & Friedman, G. Magnetic targeting for site-specific drug delivery: applications and clinical potential. Expert Opin. Drug Deliv. 6, 53–70 (2009).

    Article  CAS  PubMed  Google Scholar 

  281. Liu, Y. L., Chen, D., Shang, P. & Yin, D. C. A review of magnet systems for targeted drug delivery. J. Control. Release 302, 90–104 (2019).

    Article  CAS  PubMed  Google Scholar 

  282. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02253212 (2018).

  283. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04482803 (2023).

  284. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04240639 (2023).

  285. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04528680 (2023).

  286. Banerji, U. et al. Phase I trial of acoustic cluster therapy (ACT) with chemotherapy in patients with liver metastases of gastrointestinal origin (ACTIVATE study). J. Clin. Oncol. 39, TPS3145 (2021).

    Article  Google Scholar 

  287. Carpentier, A. et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound.Sci. Transl. Med. 8, 343re2 (2016).

    Article  PubMed  Google Scholar 

  288. Idbaih, A. et al. Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin. Cancer Res. 25, 3793–3801 (2019).

    Article  CAS  PubMed  Google Scholar 

  289. Song, C. W. Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Res. 44, 4721s–4730s (1984).

    CAS  PubMed  Google Scholar 

  290. Vaupel, P. W. & Kelleher, D. K. Pathophysiological and vascular characteristics of tumours and their importance for hyperthermia: heterogeneity is the key issue. Int. J. Hyperth. 26, 211–223 (2010).

    Article  CAS  Google Scholar 

  291. Song, C. W., Park, H. & Griffin, R. J. Improvement of tumor oxygenation by mild hyperthermia. Radiat. Res. 155, 515–528 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  292. Shakil, A., Osborn, J. L. & Song, C. W. Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia. Int. J. Radiat. Oncol. Biol. Phys. 43, 859–865 (1999).

    Article  CAS  PubMed  Google Scholar 

  293. Brizel, D. M. et al. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res. 56, 5347–5350 (1996).

    CAS  PubMed  Google Scholar 

  294. Vujaskovic, Z. et al. Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment. Int. J. Hyperth. 19, 498–506 (2003).

    Article  CAS  Google Scholar 

  295. Sun, X. et al. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual-tracer immunohistochemistry. Radiother. Oncol. 88, 269–276 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  296. Adkins, I. et al. Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells. Oncoimmunology 6, e1311433 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  297. International Collaborative Hyperthermia Group et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. Int. J. Radiat. Oncol. Biol. Phys. 35, 731–744 (1996).

    Article  Google Scholar 

  298. van der Zee, J. et al. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Lancet 355, 1119–1125 (2000).

    Article  PubMed  Google Scholar 

  299. Harima, Y. et al. A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma. Int. J. Hyperth. 17, 97–105 (2001).

    Article  CAS  Google Scholar 

  300. Horsman, M. R. & Overgaard, J. Hyperthermia: a potent enhancer of radiotherapy. Clin. Oncol. 19, 418–426 (2007).

    Article  CAS  Google Scholar 

  301. van der Zee, J. & van Rhoon, G. C. Cervical cancer: radiotherapy and hyperthermia. Int. J. Hyperth. 22, 229–234 (2006).

    Article  Google Scholar 

  302. Kong, G. et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 60, 6950–6957 (2000).

    CAS  PubMed  Google Scholar 

  303. Alvarez Secord, A. et al. Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer. Int. J. Hyperth. 21, 333–347 (2005).

    Article  CAS  Google Scholar 

  304. Vujaskovic, Z. et al. A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer. Int. J. Hyperth. 26, 514–521 (2010).

    Article  CAS  Google Scholar 

  305. Lyon, P. C. et al. Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours. J. Ther. Ultrasound 5, 28 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  306. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT00617981 (2017).

  307. Tak, W. Y. et al. Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. Clin. Cancer Res. 24, 73–83 (2018).

    Article  CAS  PubMed  Google Scholar 

  308. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03749850 (2021).

  309. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04889768 (2021).

  310. Moradi Kashkooli, F., Jakhmola, A., Hornsby, T. K., Tavakkoli, J. J. & Kolios, M. C. Ultrasound-mediated nano drug delivery for treating cancer: fundamental physics to future directions. J. Control. Release 355, 552–578 (2023).

    Article  CAS  PubMed  Google Scholar 

  311. Wu, J. et al. How nanoparticles open the paracellular route of biological barriers: mechanisms, applications, and prospects. ACS Nano 16, 15627–15652 (2022).

    Article  CAS  PubMed  Google Scholar 

  312. Sheikov, N. et al. Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier. Ultrasound Med. Biol. 32, 1399–1409 (2006).

    Article  PubMed  Google Scholar 

  313. Pandit, R. et al. Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound. J. Control. Release 327, 667–675 (2020).

    Article  CAS  PubMed  Google Scholar 

  314. Arsiwala, T. A. et al. Characterization of passive permeability after low intensity focused ultrasound mediated blood-brain barrier disruption in a preclinical model. Fluids Barriers CNS 19, 72 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  315. Givens, C. & Tzima, E. Endothelial mechanosignaling: does one sensor fit all? Antioxid. Redox Signal. 25, 373–388 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  316. Zhou, M. et al. Caveolae-mediated endothelial transcytosis across the blood-brain barrier in acute ischemic stroke. J. Clin. Med. 10, 3795 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Spisni, E. et al. Mechanosensing role of caveolae and caveolar constituents in human endothelial cells. J. Cell. Physiol. 197, 198–204 (2003).

    Article  CAS  PubMed  Google Scholar 

  318. Del Pozo, M. A., Lolo, F. N. & Echarri, A. Caveolae: mechanosensing and mechanotransduction devices linking membrane trafficking to mechanoadaptation. Curr. Opin. Cell Biol. 68, 113–123 (2021).

    Article  PubMed  Google Scholar 

  319. Bargh, J. D., Isidro-Llobet, A., Parker, J. S. & Spring, D. R. Cleavable linkers in antibody-drug conjugates. Chem. Soc. Rev. 48, 4361–4374 (2019).

    Article  CAS  PubMed  Google Scholar 

  320. Kaempffe, A. et al. Effect of conjugation site and technique on the stability and pharmacokinetics of antibody-drug conjugates. J. Pharm. Sci. 110, 3776–3785 (2021).

    Article  CAS  PubMed  Google Scholar 

  321. Chen, P. et al. Nanocarriers escaping from hyperacidified endo/lysosomes in cancer cells allow tumor-targeted intracellular delivery of antibodies to therapeutically inhibit c-MYC. Biomaterials 288, 121748 (2022).

    Article  CAS  PubMed  Google Scholar 

  322. Abbasi, S. et al. Co-encapsulation of Cas9 mRNA and guide RNA in polyplex micelles enables genome editing in mouse brain. J. Control. Release 332, 260–268 (2021).

    Article  CAS  PubMed  Google Scholar 

  323. Lin, Y., Wagner, E. & Lachelt, U. Non-viral delivery of the CRISPR/Cas system: DNA versus RNA versus RNP. Biomater. Sci. 10, 1166–1192 (2022).

    Article  CAS  PubMed  Google Scholar 

  324. Yameen, B. et al. Insight into nanoparticle cellular uptake and intracellular targeting. J. Control. Release 190, 485–499 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  325. Singh, A. P. & Shah, D. K. Measurement and mathematical characterization of cell-level pharmacokinetics of antibody-drug conjugates: a case study with trastuzumab-vc-MMAE. Drug Metab. Dispos. 45, 1120–1132 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  326. Soininen, S. K. et al. Intracellular PK/PD relationships of free and liposomal doxorubicin: quantitative analyses and PK/PD modeling. Mol. Pharm. 13, 1358–1365 (2016).

    Article  CAS  PubMed  Google Scholar 

  327. Matsumoto, Y. et al. Direct and instantaneous observation of intravenously injected substances using intravital confocal micro-videography. Biomed. Opt. Express 1, 1209–1216 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  328. Guan, H. et al. Deep-learning two-photon fiberscopy for video-rate brain imaging in freely-behaving mice. Nat. Commun. 13, 1534 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  329. Leung, C. M. et al. A guide to the organ-on-a-chip. Nat. Rev. Dis. Primers 2, 33 (2022).

    Article  CAS  Google Scholar 

  330. Kimura, H., Sakai, Y. & Fujii, T. Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab. Pharmacokinet. 33, 43–48 (2018).

    Article  CAS  PubMed  Google Scholar 

  331. Vulto, P. & Joore, J. Adoption of organ-on-chip platforms by the pharmaceutical industry. Nat. Rev. Drug Discov. 20, 961–962 (2021).

    Article  CAS  PubMed  Google Scholar 

  332. Johnston, S. T., Faria, M. & Crampin, E. J. Understanding nano-engineered particle-cell interactions: biological insights from mathematical models. Nanoscale Adv. 3, 2139–2156 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  333. Serov, N. & Vinogradov, V. Artificial intelligence to bring nanomedicine to life. Adv. Drug Deliv. Rev. 184, 114194 (2022).

    Article  CAS  PubMed  Google Scholar 

  334. Grzegorzewski, J. et al. PK-DB: pharmacokinetics database for individualized and stratified computational modeling. Nucleic Acids Res. 49, D1358–D1364 (2021).

    Article  CAS  PubMed  Google Scholar 

  335. Cheng, Y. H., He, C., Riviere, J. E., Monteiro-Riviere, N. A. & Lin, Z. Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic modeling and simulation approach. ACS Nano 14, 3075–3095 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. Lin, Z., Aryal, S., Cheng, Y. H. & Gesquiere, A. J. Integration of in vitro and in vivo models to predict cellular and tissue dosimetry of nanomaterials using physiologically based pharmacokinetic modeling. ACS Nano 16, 19722–19754 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  337. Bronte, V. & Pittet, M. J. The spleen in local and systemic regulation of immunity. Immunity 39, 806–818 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  338. Rajan, R. et al. Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate. J. Control. Release 271, 139–148 (2018).

    Article  CAS  PubMed  Google Scholar 

  339. Zajac, E. et al. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood 122, 4054–4067 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  340. Wu, K., Liu, J., Johnson, R. N., Yang, J. & Kopecek, J. Drug-free macromolecular therapeutics: induction of apoptosis by coiled-coil-mediated cross-linking of antigens on the cell surface. Angew. Chem. Int. Ed. Engl. 49, 1451–1455 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  341. Li, H. et al. M2-type exosomes nanoparticles for rheumatoid arthritis therapy via macrophage re-polarization. J. Control. Release 341, 16–30 (2022).

    Article  CAS  PubMed  Google Scholar 

  342. Sun, D. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606–1614 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  343. Zhao, J. et al. Mesenchymal stem cells-derived exosomes as dexamethasone delivery vehicles for autoimmune hepatitis therapy. Front. Bioeng. Biotechnol. 9, 650376 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  344. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT01294072 (2021).

  345. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05523011 (2022).

  346. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05499156 (2022).

  347. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04491240 (2020).

  348. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04798716 (2022).

  349. Bohle, A. et al. Human glomerular structure under normal conditions and in isolated glomerular disease. Kidney Int. Suppl. 67, S186–S188 (1998).

    Article  CAS  PubMed  Google Scholar 

  350. Blouin, A., Bolender, R. P. & Weibel, E. R. Distribution of organelles and membranes between hepatocytes and non-hepatocytes in rat-liver parenchyma — a stereological study. J. Cell Bio. 72, 441–455 (1977).

    Article  CAS  Google Scholar 

  351. Du, B. et al. Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regime. Nat. Nanotechnol. 12, 1096–1102 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  352. Szafranska, K., Kruse, L. D., Holte, C. F., McCourt, P. & Zapotoczny, B. The whole story about fenestrations in LSEC. Front. Physiol. 12, 735573 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  353. Bhandari, S., Larsen, A. K., McCourt, P., Smedsrod, B. & Sorensen, K. K. The scavenger function of liver sinusoidal endothelial cells in health and disease. Front. Physiol. 12, 757469 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  354. Halamoda-Kenzaoui, B. et al. Methodological needs in the quality and safety characterisation of nanotechnology-based health products: priorities for method development and standardisation. J. Control. Release 336, 192–206 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  355. Chen, H. M., Zhang, W. Z., Zhu, G. Z., Xie, J. & Chen, X. Y. Rethinking cancer nanotheranostics. Nat. Rev. Mater. 2, 17024 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) (Project No. 16 cm0106202h0001; H.C. and K.K) from the Japan Agency for Medical Research and Development (AMED). The study was partially supported by Grants-in-Aid for Scientific Research (B) (20H04524; H.C.), Grants-in-Aid for Exploratory Research (H.C.), and Grants-in-Aid for Scientific Research (B) (23H03740; J.L.) from the Japan Society for the Promotion of Science (JSPS) and a grant for young researchers from the Institute for Materials Chemistry and Engineering at Kyushu University.

Author information

Author notes

  1. These authors contributed equally: Horacio Cabral, Junjie Li.

Authors and Affiliations

  1. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Horacio Cabral & Kanjiro Miyata

  2. Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan

    Junjie Li

  3. Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Kanjiro Miyata

  4. Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

    Kazunori Kataoka

Authors
  1. Horacio Cabral
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junjie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kanjiro Miyata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazunori Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.C., J.L. and K.M. wrote the manuscript. H.C. and J.L. prepared the figures and tables. K.K. supervised the project. All authors made a substantial contribution to the discussion of content and editing of the manuscript.

Corresponding authors

Correspondence to Horacio Cabral or Kazunori Kataoka.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Bioengineering thanks Olivia Merkel and the other, anonymous, reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cabral, H., Li, J., Miyata, K. et al. Controlling the biodistribution and clearance of nanomedicines. Nat Rev Bioeng 2, 214–232 (2024). https://doi.org/10.1038/s44222-023-00138-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44222-023-00138-1

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research