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:

Designing drug delivery systems for cell therapy

Nature Reviews Bioengineering (2024)Cite this article

Subjects

Abstract

Cell therapies, such as immune cell and stem cell therapies, are being preclinically and clinically explored for the treatment of various diseases, but are often limited by low efficacy and safety concerns. Drug delivery systems at the nanoscale, microscale and macroscale can be designed to improve cell therapies by optimizing pharmacokinetics, cell function and cell viability, and by preventing cell exhaustion and immunogenicity. In this Review, we discuss the engineering of drug delivery systems at various scales to improve the biological functions of therapeutic cells, modulate tissue environments to promote the survival and efficacy of therapeutic cells, enable targeted delivery of therapeutic agents by transferred cells and provide protective barriers for cells in vivo. We further outline crucial milestones for the clinical translation of cell therapies integrated with drug delivery systems and highlight manufacturing challenges.

Key points

  • Integrating drug delivery systems with cell therapy may improve the precision, minimize side effects and promote therapeutic cell functions of cell therapy treatments.

  • Drug delivery systems can be designed to modulate transferred cell functions, influence surrounding tissues and protect cells from adverse in vivo conditions.

  • Factors to consider for the formulation of drug delivery system include therapeutic cell types, the target tissue or organ, the nature of the therapeutic agents and the desired release kinetics.

  • Nanoscale, microscale and macroscale drug delivery platforms can be designed to improve cell survival, function and targeted delivery.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Drug delivery to modulate the biological functions of transferred cells.
Fig. 2: Cargo delivery to regulate tissue surrounding transferred cells.
Fig. 3: Drug delivery technologies to protect therapeutic cells.

Similar content being viewed by others

References

  1. Martino, M. et al. CART-cell therapy: recent advances and new evidence in multiple myeloma. Cancers 13, 2639 (2021).

    Article  Google Scholar 

  2. Sivandzade, F. & Cucullo, L. Regenerative stem cell therapy for neurodegenerative diseases: an overview. Int. J. Mol. Sci. 22, 2153 (2021).

    Article  Google Scholar 

  3. Kitada, T., DiAndreth, B., Teague, B. & Weiss, R. Programming gene and engineered-cell therapies with synthetic biology. Science 359, eaad1067 (2018).

    Article  Google Scholar 

  4. Weber, E. W., Maus, M. V. & Mackall, C. L. The emerging landscape of immune cell therapies. Cell 181, 46–62 (2020). This perspective provides an overview of current developments in immune cell therapies for cancer, infectious diseases and autoimmunity, and highlights cellular engineering advances addressing key challenges.

    Article  Google Scholar 

  5. Fischbach, M. A., Bluestone, J. A. & Lim, W. A. Cell-based therapeutics: the next pillar of medicine. Sci. Transl. Med. 5, 179ps7 (2013).

    Article  Google Scholar 

  6. Zhao, Z., Ukidve, A., Kim, J. & Mitragotri, S. Targeting strategies for tissue-specific drug delivery. Cell 181, 151–167 (2020).

    Article  Google Scholar 

  7. Mount, N. M., Ward, S. J., Kefalas, P. & Hyllner, J. Cell-based therapy technology classifications and translational challenges. Philos. Trans. R. Soc. B: Biol. Sci. 370, 20150017 (2015).

    Article  Google Scholar 

  8. Wang, L. L. W. et al. Cell therapies in the clinic. Bioeng. Transl. Med. 6, e10214 (2021). This review highlights the diversity and advantages of cell therapies, discusses 28 globally approved products and their clinical uses, analyses more than 1,700 active clinical trials and addresses the major biological, manufacturing and regulatory challenges in their clinical translation.

    Article  MathSciNet  Google Scholar 

  9. Vargason, A. M., Anselmo, A. C. & Mitragotri, S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 5, 951–967 (2021).

    Article  Google Scholar 

  10. Wang, H. & Mooney, D. J. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nat. Mater. 17, 761–772 (2018).

    Article  Google Scholar 

  11. Li, Z. et al. Cell‐based delivery systems: emerging carriers for immunotherapy. Adv. Funct. Mater. 31, 2100088 (2021).

    Article  Google Scholar 

  12. Yang, L., Yang, Y., Chen, Y., Xu, Y. & Peng, J. Cell-based drug delivery systems and their in vivo fate. Adv. Drug Deliv. Rev. 187, 114394 (2022).

    Article  Google Scholar 

  13. Li, J. et al. Implantable and injectable biomaterial scaffolds for cancer immunotherapy. Front. Bioeng. Biotechnol. 8, 612950 (2020).

    Article  Google Scholar 

  14. Adeyemi, S. A. & Choonara, Y. E. Current advances in cell therapeutics: a biomacromolecules application perspective. Expert. Opin. Drug. Deliv. 19, 521–538 (2022).

    Article  Google Scholar 

  15. Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).

    Article  Google Scholar 

  16. Sterner, R. C. & Sterner, R. M. CAR-T cell therapy: current limitations and potential strategies. Blood cancer J. 11, 69 (2021).

    Article  MathSciNet  Google Scholar 

  17. Arjomandnejad, M., Kopec, A. L. & Keeler, A. M. CAR-T regulatory (CAR-Treg) cells: engineering and applications. Biomedicines 10, 287 (2022).

    Article  Google Scholar 

  18. Romano, M., Fanelli, G., Albany, C. J., Giganti, G. & Lombardi, G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front. Immunol. 10, 43 (2019).

    Article  Google Scholar 

  19. Zhang, L., Meng, Y., Feng, X. & Han, Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomarker Res. 10, 1–19 (2022).

    Article  Google Scholar 

  20. Bald, T., Krummel, M. F., Smyth, M. J. & Barry, K. C. The NK cell–cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nat. Immunol. 21, 835–847 (2020).

    Article  Google Scholar 

  21. Na, Y. R., Kim, S. W. & Seok, S. H. A new era of macrophage-based cell therapy. Exp. Mol. Med. 55, 1945–1954 (2023).

    Article  Google Scholar 

  22. Lee, S., Kivimäe, S., Dolor, A. & Szoka, F. C. Macrophage-based cell therapies: the long and winding road. J. Control. Rel. 240, 527–540 (2016).

    Article  Google Scholar 

  23. Hoang, D. M. et al. Stem cell-based therapy for human diseases. Signal. Transduct. Target. Ther. 7, 272 (2022).

    Article  Google Scholar 

  24. Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. & Rybak, Z. Stem cells: past, present, and future. Stem Cell Res. Ther. 10, 1–22 (2019).

    Article  Google Scholar 

  25. Basile, G. et al. Emerging diabetes therapies: bringing back the β-cells. Mol. Metab. 60, 101477 (2022).

    Article  Google Scholar 

  26. Yu, H., Yang, Z., Li, F., Xu, L. & Sun, Y. Cell-mediated targeting drugs delivery systems. Drug. Deliv. 27, 1425–1437 (2020).

    Article  Google Scholar 

  27. Yousefpour, P., Ni, K. & Irvine, D. J. Targeted modulation of immune cells and tissues using engineered biomaterials. Nat. Rev. Bioeng. 1, 107–124 (2023).

    Article  Google Scholar 

  28. Li, R., Chen, Z., Li, J., Dai, Z. & Yu, Y. Nano-drug delivery systems for T cell-based immunotherapy. Nano Today 46, 101621 (2022).

    Article  Google Scholar 

  29. Ahn, Y. H. et al. A three-dimensional hyaluronic acid-based niche enhances the therapeutic efficacy of human natural killer cell-based cancer immunotherapy. Biomaterials 247, 119960 (2020).

    Article  Google Scholar 

  30. Prakash, S. et al. Polymer micropatches as natural killer cell engagers for tumor therapy. ACS Nano 17, 15918–15930 (2023).

    Article  Google Scholar 

  31. Sung, S., Steele, L. A., Risser, G. E. & Spiller, K. L. Biomaterial-assisted macrophage cell therapy for regenerative medicine. Adv. Drug Deliv. Rev. 199, 114979 (2023).

    Article  Google Scholar 

  32. Liang, T. et al. Recent advances in macrophage-mediated drug delivery systems. Int. J. Nanomed. 16, 2703 (2021).

    Article  Google Scholar 

  33. Li, Y. et al. Clinical progress and advanced research of red blood cells based drug delivery system. Biomaterials 279, 121202 (2021).

    Article  Google Scholar 

  34. Kharbikar, B. N., Mohindra, P. & Desai, T. A. Biomaterials to enhance stem cell transplantation. Cell Stem Cell 29, 692–721 (2022).

    Article  Google Scholar 

  35. Quizon, M. J. & García, A. J. Engineering β cell replacement therapies for type 1 diabetes: biomaterial advances and considerations for macroscale constructs. Annu. Rev. Pathol. Mech. Dis. 17, 485–513 (2022).

    Article  Google Scholar 

  36. Adebowale, K. et al. Materials for cell surface engineering. Adv. Mater. https://doi.org/10.1002/adma.202210059 (2023). This review summarizes recent advances in decorating cell surfaces with nanoparticles, microparticles and polymeric coatings, focusing on enhancing carrier cells and their therapeutic effects.

  37. Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).

    Article  Google Scholar 

  38. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).

    Article  Google Scholar 

  39. Scott, M. D., Murad, K. L., Koumpouras, F., Talbot, M. & Eaton, J. W. Chemical camouflage of antigenic determinants: stealth erythrocytes. Proc. Natl Acad. Sci. USA 94, 7566–7571 (1997).

    Article  Google Scholar 

  40. Pan, C. et al. Polymerization‐mediated multifunctionalization of living cells for enhanced cell‐based therapy. Adv. Mater. 33, 2007379 (2021).

    Article  Google Scholar 

  41. Shields, C. W. et al. Cellular backpacks for macrophage immunotherapy. Sci. Adv. 6, eaaz6579 (2020).

    Article  Google Scholar 

  42. Kapate, N. et al. Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury. PNAS Nexus 3, pgad434 (2024).

    Article  Google Scholar 

  43. Kapate, N. et al. Polymer backpack‐loaded tissue infiltrating monocytes for treating cancer. Adv. Healthc. Mater. 2304144 https://doi.org/10.1002/adhm.202304144 (2024).

  44. Farina, M., Alexander, J. F., Thekkedath, U., Ferrari, M. & Grattoni, A. Cell encapsulation: overcoming barriers in cell transplantation in diabetes and beyond. Adv. Drug Deliv. Rev. 139, 92–115 (2019). This review summarizes encapsulation strategies from academic and industrial research, including technologies in advanced preclinical and clinical phases, and highlights stimulus-responsive systems for improved therapeutic delivery in cell transplantation.

    Article  Google Scholar 

  45. Sun, L. et al. Induced cardiomyocytes-integrated conductive microneedle patch for treating myocardial infarction. Chem. Eng. J. 414, 128723 (2021).

    Article  Google Scholar 

  46. Lathuiliere, A. et al. A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies. Brain 139, 1587–1604 (2016).

    Article  Google Scholar 

  47. Yang, L. et al. A biodegradable hybrid inorganic nanoscaffold for advanced stem cell therapy. Nat. Commun. 9, 3147 (2018).

    Article  Google Scholar 

  48. Ye, Y. et al. Microneedles integrated with pancreatic cells and synthetic glucose‐signal amplifiers for smart insulin delivery. Adv. Mater. 28, 3115–3121 (2016).

    Article  Google Scholar 

  49. Xue, D., Hsu, E., Fu, Y.-X. & Peng, H. Next-generation cytokines for cancer immunotherapy. Antib. Ther. 4, 123–133 (2021).

    Google Scholar 

  50. Jones, R. B. et al. Antigen recognition-triggered drug delivery mediated by nanocapsule-functionalized cytotoxic T-cells. Biomaterials 117, 44–53 (2017).

    Article  Google Scholar 

  51. Xie, Y.-Q. et al. Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells. Biomater. Sci. 7, 1345–1357 (2019).

    Article  Google Scholar 

  52. Eskandari, S. K. et al. Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter. Sci. Transl. Med. 12, eaaw4744 (2020).

    Article  Google Scholar 

  53. Liu, Y. et al. Cytokine conjugation to enhance T cell therapy. Proc. Natl Acad. Sci. USA 120, e2213222120 (2023).

    Article  Google Scholar 

  54. Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020).

    Article  Google Scholar 

  55. Stephan, M. T., Stephan, S. B., Bak, P., Chen, J. & Irvine, D. J. Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles. Biomaterials 33, 5776–5787 (2012).

    Article  Google Scholar 

  56. Hao, M. et al. Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy. Sci. Transl. Med. 12, eaaz6667 (2020).

    Article  Google Scholar 

  57. Trowbridge, J. J., Xenocostas, A., Moon, R. T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat. Med. 12, 89–98 (2006).

    Article  Google Scholar 

  58. Loukogeorgakis, S. P. et al. Donor cell engineering with GSK3 inhibitor-loaded nanoparticles enhances engraftment after in utero transplantation. Blood 134, 1983–1995 (2019).

    Article  Google Scholar 

  59. Yu, D. et al. Hydrogen‐bonded organic framework (HOF)‐based single‐neural stem cell encapsulation and transplantation to remodel impaired neural networks. Angew. Chem. 134, e202201485 (2022).

    Article  Google Scholar 

  60. Kapate, N. et al. A backpack-based myeloid cell therapy for multiple sclerosis. Proc. Natl Acad. Sci. USA 120, e2221535120 (2023).

    Article  Google Scholar 

  61. Liu, S. et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. J. Hematol. Oncol. 14, 1–17 (2021).

    Article  Google Scholar 

  62. Kumbhojkar, N. et al. Neutrophils bearing adhesive polymer micropatches as a drug-free cancer immunotherapy. Nat. Biomed. Eng. 8, 579–592 (2024).

    Article  Google Scholar 

  63. Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).

    Article  Google Scholar 

  64. Chen, X. et al. Secretion of bispecific protein of anti-PD-1 fused with TGF-β trap enhances antitumor efficacy of CAR-T cell therapy. Mol. Ther. Oncol. 21, 144–157 (2021).

    Article  Google Scholar 

  65. Ghasemi, A. et al. Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy. Nat. Cancer 5, 240–261 (2023).

    Article  Google Scholar 

  66. Agarwalla, P. et al. Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells. Nat. Biotechnol. 40, 1250–1258 (2022).

    Article  Google Scholar 

  67. Anselmo, A. C. et al. Delivering nanoparticles to lungs while avoiding liver and spleen through adsorption on red blood cells. ACS Nano 7, 11129–11137 (2013).

    Article  Google Scholar 

  68. Anselmo, A. C. et al. Exploiting shape, cellular-hitchhiking and antibodies to target nanoparticles to lung endothelium: synergy between physical, chemical and biological approaches. Biomaterials 68, 1–8 (2015).

    Article  Google Scholar 

  69. Brenner, J. S. et al. Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude. Nat. Commun. 9, 2684 (2018).

    Article  Google Scholar 

  70. Ukidve, A. et al. Erythrocyte-driven immunization via biomimicry of their natural antigen-presenting function. Proc. Natl Acad. Sci. USA 117, 17727–17736 (2020).

    Article  Google Scholar 

  71. Zhao, Z., Ukidve, A., Gao, Y., Kim, J. & Mitragotri, S. Erythrocyte leveraged chemotherapy (ELeCt): nanoparticle assembly on erythrocyte surface to combat lung metastasis. Sci. Adv. 5, eaax9250 (2019).

    Article  Google Scholar 

  72. Zhao, Z. et al. Systemic tumour suppression via the preferential accumulation of erythrocyte-anchored chemokine-encapsulating nanoparticles in lung metastases. Nat. Biomed. Eng. 5, 441–454 (2021).

    Article  Google Scholar 

  73. Ding, Y. et al. RBC-hitchhiking chitosan nanoparticles loading methylprednisolone for lung-targeting delivery. J. Control, Rel. 341, 702–715 (2022).

    Article  Google Scholar 

  74. Wang, C. et al. Multifunctional theranostic red blood cells for magnetic‐field‐enhanced in vivo combination therapy of cancer. Adv. Mater. 26, 4794–4802 (2014).

    Article  Google Scholar 

  75. Ferguson, L. T. et al. Dual affinity to RBCs and target cells (DART) enhances both organ-and cell type-targeting of intravascular nanocarriers. ACS Nano 16, 4666–4683 (2022).

    Article  Google Scholar 

  76. Zhao, Z. et al. Engineering of living cells with polyphenol‐functionalized biologically active nanocomplexes. Adv. Mater. 32, 2003492 (2020).

    Article  Google Scholar 

  77. Zhao, Z. et al. Red blood cell anchoring enables targeted transduction and re‐administration of AAV‐mediated gene therapy. Adv. Sci. 9, 2201293 (2022).

    Article  Google Scholar 

  78. Zelepukin, I. et al. Nanoparticle-based drug delivery via RBC-hitchhiking for the inhibition of lung metastases growth. Nanoscale 11, 1636–1646 (2019).

    Article  Google Scholar 

  79. Schmid, D. et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat. Commun. 8, 1–12 (2017).

    Article  Google Scholar 

  80. Huang, B. et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci. Transl. Med. 7, 291ra94 (2015).

    Article  Google Scholar 

  81. Shi, C. et al. Trojan horse nanocapsule enabled in situ modulation of the phenotypic conversion of TH17 cells to Treg cells for the treatment of multiple sclerosis in mice. Adv. Mater. 35, 2210262 (2023).

    Article  Google Scholar 

  82. Gao, C. et al. Supramolecular macrophage–liposome marriage for cell‐hitchhiking delivery and immunotherapy of acute pneumonia and melanoma. Adv. Funct. Mater. 31, 2102440 (2021).

    Article  Google Scholar 

  83. Yang, L. et al. Live macrophage-delivered doxorubicin-loaded liposomes effectively treat triple-negative breast cancer. ACS Nano 16, 9799–9809 (2022).

    Article  Google Scholar 

  84. Im, S. et al. Harnessing the formation of natural killer–tumor cell immunological synapses for enhanced therapeutic effect in solid tumors. Adv. Mater. 32, 2000020 (2020).

    Article  Google Scholar 

  85. Mosquera, J., García, I. & Liz-Marzán, L. M. Cellular uptake of nanoparticles versus small molecules: a matter of size. Acc. Chem. Res. 51, 2305–2313 (2018).

    Article  Google Scholar 

  86. Rennick, J. J., Johnston, A. P. & Parton, R. G. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat. Nanotechnol. 16, 266–276 (2021).

    Article  Google Scholar 

  87. Dou, H. et al. Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery. Blood 108, 2827–2835 (2006).

    Article  Google Scholar 

  88. Choi, M.-R. et al. A cellular Trojan horse for delivery of therapeutic nanoparticles into tumors. Nano Lett. 7, 3759–3765 (2007).

    Article  Google Scholar 

  89. Evans, M. A. et al. Macrophage‐mediated delivery of hypoxia‐activated prodrug nanoparticles. Adv. Ther. 3, 1900162 (2020).

    Article  Google Scholar 

  90. Qi, Y., Yan, X., Xia, T. & Liu, S. Use of macrophage as a Trojan horse for cancer nanotheranostics. Mater. Des. 198, 109388 (2021).

    Article  Google Scholar 

  91. Mantovani, A., Allavena, P., Marchesi, F. & Garlanda, C. Macrophages as tools and targets in cancer therapy. Nat. Rev. Drug. Discov. 21, 799–820 (2022).

    Article  Google Scholar 

  92. Choi, J. et al. Use of macrophages to deliver therapeutic and imaging contrast agents to tumors. Biomaterials 33, 4195–4203 (2012).

    Article  Google Scholar 

  93. De Oliveira, S., Rosowski, E. E. & Huttenlocher, A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat. Rev. Immunol. 16, 378–391 (2016).

    Article  Google Scholar 

  94. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    Article  Google Scholar 

  95. Xue, J. et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat. Nanotechnol. 12, 692 (2017).

    Article  Google Scholar 

  96. Luo, Z. et al. Neutrophil hitchhiking for drug delivery to the bone marrow. Nat. Nanotechnol. 18, 647–656 (2023).

    Article  Google Scholar 

  97. Shi, M. et al. Dual functional monocytes modulate bactericidal and anti‐inflammation process for severe osteomyelitis treatment. Small 16, 1905185 (2020).

    Article  Google Scholar 

  98. Kim, H. et al. Gold nanoparticle‐carrying T cells for the combined immuno‐photothermal therapy. Small 19, 2301377 (2023).

    Article  Google Scholar 

  99. Wu, M. et al. MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma. Nat. Commun. 9, 4777 (2018).

    Article  Google Scholar 

  100. Sun, P. et al. A smart nanoparticle-laden and remote-controlled self-destructive macrophage for enhanced chemo/chemodynamic synergistic therapy. ACS Nano 14, 13894–13904 (2020).

    Article  Google Scholar 

  101. Ye, B. et al. Neutrophils mediated multistage nanoparticle delivery for prompting tumor photothermal therapy. J. Nanobiotechnol. 18, 1–14 (2020).

    Article  Google Scholar 

  102. Li, Z. et al. Small gold nanorods laden macrophages for enhanced tumor coverage in photothermal therapy. Biomaterials 74, 144–154 (2016).

    Article  Google Scholar 

  103. Li, Z. et al. Cell-borne 2D nanomaterials for efficient cancer targeting and photothermal therapy. Biomaterials 133, 37–48 (2017).

    Article  Google Scholar 

  104. Pinho, S., Macedo, M. H., Rebelo, C., Sarmento, B. & Ferreira, L. Stem cells as vehicles and targets of nanoparticles. Drug. Discov. Today 23, 1071–1078 (2018).

    Article  Google Scholar 

  105. Cao, B., Yang, M., Zhu, Y., Qu, X. & Mao, C. Stem cells loaded with nanoparticles as a drug carrier for in vivo breast cancer therapy. Adv. Mater. 26, 4627–4631 (2014).

    Article  Google Scholar 

  106. Lai, Y.-H. et al. Stem cell–nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy. Nat. Commun. 14, 285 (2023).

    Article  Google Scholar 

  107. Anselmo, A. C. et al. Monocyte-mediated delivery of polymeric backpacks to inflamed tissues: a generalized strategy to deliver drugs to treat inflammation. J. Control. Rel. 199, 29–36 (2015).

    Article  Google Scholar 

  108. Gilbert, J. B., O’Brien, J. S., Suresh, H. S., Cohen, R. E. & Rubner, M. F. Orientation‐specific attachment of polymeric microtubes on cell surfaces. Adv. Mater. 25, 5948–5952 (2013).

    Article  Google Scholar 

  109. Polak, R. et al. Liposome‐loaded cell backpacks. Adv. Healthc. Mater. 4, 2832–2841 (2015).

    Article  Google Scholar 

  110. Wang, L. L.-W. et al. Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs. Sci. Transl. Med. 16, eadk5413 (2024).

    Article  Google Scholar 

  111. Alapan, Y. et al. Soft erythrocyte-based bacterial microswimmers for cargo delivery. Sci. Robot. 3, eaar4423 (2018).

    Article  Google Scholar 

  112. Tang, J. et al. Cardiac cell–integrated microneedle patch for treating myocardial infarction. Sci. Adv. 4, eaat9365 (2018).

    Article  Google Scholar 

  113. Bagó, J. R. et al. Electrospun nanofibrous scaffolds increase the efficacy of stem cell-mediated therapy of surgically resected glioblastoma. Biomaterials 90, 116–125 (2016).

    Article  Google Scholar 

  114. Xue, Y. et al. LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing. Nat. Commun. 15, 739 (2024).

    Article  Google Scholar 

  115. Webber, M. J., Khan, O. F., Sydlik, S. A., Tang, B. C. & Langer, R. A perspective on the clinical translation of scaffolds for tissue engineering. Ann. Biomed. Eng. 43, 641–656 (2015).

    Article  Google Scholar 

  116. Drury, J. L. & Mooney, D. J. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 24, 4337–4351 (2003).

    Article  Google Scholar 

  117. Lee, H. et al. A decade of advances in single‐cell nanocoating for mammalian cells. Adv. Healthc. Mater. 10, 2100347 (2021).

    Article  Google Scholar 

  118. Singh, A. et al. Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid. Nat. Mater. 13, 988–995 (2014).

    Article  Google Scholar 

  119. Rossi, N. A., Constantinescu, I., Brooks, D. E., Scott, M. D. & Kizhakkedathu, J. N. Enhanced cell surface polymer grafting in concentrated and nonreactive aqueous polymer solutions. J. Am. Chem. Soc. 132, 3423–3430 (2010).

    Article  Google Scholar 

  120. Kim, H. et al. General and facile coating of single cells via mild reduction. J. Am. Chem. Soc. 140, 1199–1202 (2018).

    Article  Google Scholar 

  121. Mahal, L. K., Yarema, K. J. & Bertozzi, C. R. Engineering chemical reactivity on cell surfaces through oligosaccharide biosynthesis. Science 276, 1125–1128 (1997).

    Article  Google Scholar 

  122. Wilson, J. T., Krishnamurthy, V. R., Cui, W., Qu, Z. & Chaikof, E. L. Noncovalent cell surface engineering with cationic graft copolymers. J. Am. Chem. Soc. 131, 18228–18229 (2009).

    Article  Google Scholar 

  123. Teramura, Y., Kaneda, Y., Totani, T. & Iwata, H. Behavior of synthetic polymers immobilized on a cell membrane. Biomaterials 29, 1345–1355 (2008).

    Article  Google Scholar 

  124. Park, J. et al. Engineering the surface of therapeutic “living” cells. Chem. Rev. 118, 1664–1690 (2018).

    Article  Google Scholar 

  125. Le, Y. & Scott, M. D. Immunocamouflage: the biophysical basis of immunoprotection by grafted methoxypoly(ethylene glycol) (mPEG). Acta Biomater. 6, 2631–2641 (2010).

    Article  Google Scholar 

  126. Yang, S. H. et al. Mussel-inspired encapsulation and functionalization of individual yeast cells. J. Am. Chem. Soc. 133, 2795–2797 (2011).

    Article  Google Scholar 

  127. Wang, D., Toyofuku, W. M. & Scott, M. D. The potential utility of methoxypoly (ethylene glycol)-mediated prevention of rhesus blood group antigen RhD recognition in transfusion medicine. Biomaterials 33, 3002–3012 (2012).

    Article  Google Scholar 

  128. Bochenek, M. A. et al. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat. Biomed. Eng. 2, 810–821 (2018).

    Article  Google Scholar 

  129. Veiseh, O. et al. Size-and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643–651 (2015).

    Article  Google Scholar 

  130. Dhawan, A. et al. Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children. J. Hepatol. 72, 877–884 (2020).

    Article  Google Scholar 

  131. Snow, B. et al. A phase IIb, randomised, double-blind, placebo-controlled, dose-ranging investigation of the safety and efficacy of NTCELL® [immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson’s disease. Parkinsonism Relat. Disord. 61, 88–93 (2019).

    Article  Google Scholar 

  132. de Vos, P., Lazarjani, H. A., Poncelet, D. & Faas, M. M. Polymers in cell encapsulation from an enveloped cell perspective. Adv. Drug Deliv. Rev. 67, 15–34 (2014).

    Article  Google Scholar 

  133. Chaimov, D. et al. Innovative encapsulation platform based on pancreatic extracellular matrix achieve substantial insulin delivery. J. Control. Rel. 257, 91–101 (2017).

    Article  Google Scholar 

  134. Calafiore, R. et al. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 29, 137–138 (2006).

    Article  Google Scholar 

  135. Basta, G. et al. Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 34, 2406–2409 (2011).

    Article  Google Scholar 

  136. Tuch, B. E. et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 32, 1887–1889 (2009).

    Article  Google Scholar 

  137. Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345–352 (2016).

    Article  Google Scholar 

  138. Matlaga, B. F., Yasenchak, L. P. & Salthouse, T. N. Tissue response to implanted polymers: the significance of sample shape. J. Biomed. Mater. Res. 10, 391–397 (1976).

    Article  Google Scholar 

  139. Shapiro, A. J. et al. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep. Med. 2, 100466 (2021).

    Article  Google Scholar 

  140. Chang, R. et al. Nanoporous immunoprotective device for stem-cell-derived β-cell replacement therapy. ACS Nano 11, 7747–7757 (2017).

    Article  Google Scholar 

  141. Sivaraj, D. et al. Hydrogel scaffolds to deliver cell therapies for wound healing. Front. Bioeng. Biotechnol. 9, 660145 (2021).

    Article  Google Scholar 

  142. Garg, R. K. et al. Capillary force seeding of hydrogels for adipose-derived stem cell delivery in wounds. Stem Cell Transl. Med. 3, 1079–1089 (2014).

    Article  Google Scholar 

  143. Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic. Bioeng. Transl. Med. 1, 10–29 (2016).

    Article  Google Scholar 

  144. Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic: an update. Bioeng. Transl. Med. 4, e10143 (2019).

    Article  Google Scholar 

  145. Mandal, A., Clegg, J. R., Anselmo, A. C. & Mitragotri, S. Hydrogels in the clinic. Bioeng. Transl. Med. 5, e10158 (2020).

    Article  Google Scholar 

  146. Bailey, S. R. & Maus, M. V. Gene editing for immune cell therapies. Nat. Biotechnol. 37, 1425–1434 (2019).

    Article  Google Scholar 

  147. Ellis, G. I., Sheppard, N. C. & Riley, J. L. Genetic engineering of T cells for immunotherapy. Nat. Rev. Genet. 22, 427–447 (2021).

    Article  Google Scholar 

  148. Hamilton, E. et al. PRIME™ IL-15 (RPTR-147): preliminary clinical results and biomarker analysis from a first-in-human phase 1 study of IL-15 loaded peripherally-derived autologous T cell therapy in solid tumor patients. J. Immunother. Cancer 8, A479–A480 (2020).

    Google Scholar 

  149. Falcetti, C. & Offner, O. Torben Straight Nissen joins Repertoire® Immune Medicines as Chief Executive Officer. Company refocusing on the potential of its DECODE™ platform to develop transformative immune medicines. businesswire https://go.nature.com/4cYiABC (2022).

  150. Aijaz, A. et al. Biomanufacturing for clinically advanced cell therapies. Nat. Biomed. Eng. 2, 362–376 (2018).

    Article  Google Scholar 

  151. Batty, C. J., Bachelder, E. M. & Ainslie, K. M. Historical perspective of clinical nano and microparticle formulations for delivery of therapeutics. Trends Mol. Med. 27, 516–519 (2021).

    Article  Google Scholar 

  152. Stewart, S. A., Domínguez-Robles, J., Donnelly, R. F. & Larrañeta, E. Implantable polymeric drug delivery devices: classification, manufacture, materials, and clinical applications. Polymers 10, 1379 (2018).

    Article  Google Scholar 

  153. Li, J., Wu, C., Chu, P. K. & Gelinsky, M. 3D printing of hydrogels: rational design strategies and emerging biomedical applications. Mater. Sci. Eng. R: Rep. 140, 100543 (2020).

    Article  Google Scholar 

  154. Zhang, H. et al. Microfluidics for nano-drug delivery systems: from fundamentals to industrialization. Acta Pharm. Sin. B 13, 3277–3299 (2023).

    Article  Google Scholar 

  155. Kim, H. U., Roh, Y. H., Mun, S. J. & Bong, K. W. Discontinuous dewetting in a degassed mold for fabrication of homogeneous polymeric microparticles. ACS Appl. Mater. Interfaces 12, 53318–53327 (2020).

    Article  Google Scholar 

  156. Wang, J.-Y. & Wang, Y. Particle replication in non-wetting templates: a platform for engineering shape-and size-specific janus particles. Angew. Chem. Int. Ed. Engl. 52, 6580–6589 (2012).

    Google Scholar 

  157. Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 1, 16071 (2016).

    Article  Google Scholar 

  158. Kakkar, A., Traverso, G., Farokhzad, O. C., Weissleder, R. & Langer, R. Evolution of macromolecular complexity in drug delivery systems. Nat. Rev. Chem. 1, 63 (2017).

    Article  Google Scholar 

  159. Zhang, Y., Chan, H. F. & Leong, K. W. Advanced materials and processing for drug delivery: the past and the future. Adv. Drug Deliv. Rev. 65, 104–120 (2013).

    Article  Google Scholar 

  160. Chen, R. et al. Biomaterial-assisted scalable cell production for cell therapy. Biomaterials 230, 119627 (2020). This review discusses how biomaterials enhance cell production by creating biomimetic environments that support cell adhesion and proliferation, maintain cell characteristics, and improve production efficiency and quality control through automated, Good Manufacturing Practice-compliant methods.

    Article  Google Scholar 

  161. Roh, K.-H., Nerem, R. M. & Roy, K. Biomanufacturing of therapeutic cells: state of the art, current challenges, and future perspectives. Annu. Rev. Chem. Biomol. Eng. 7, 455–478 (2016).

    Article  Google Scholar 

  162. Chen, A. K.-L., Chen, X., Choo, A. B. H., Reuveny, S. & Oh, S. K. W. Critical microcarrier properties affecting the expansion of undifferentiated human embryonic stem cells. Stem Cell Res. 7, 97–111 (2011).

    Article  Google Scholar 

  163. Carletti, E., Motta, A. & Migliaresi, C. Scaffolds for tissue engineering and 3D cell culture. Methods Mol. Biol. 695, 17–39 (2011).

    Article  Google Scholar 

  164. Cheung, A. S., Zhang, D. K., Koshy, S. T. & Mooney, D. J. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat. Biotechnol. 36, 160–169 (2018).

    Article  Google Scholar 

  165. Ashley, E. A. Towards precision medicine. Nat. Rev. Genet. 17, 507–522 (2016).

    Article  Google Scholar 

  166. Manzari, M. T. et al. Targeted drug delivery strategies for precision medicines. Nat. Rev. Mater. 6, 351–370 (2021).

    Article  Google Scholar 

  167. Facklam, A. L., Volpatti, L. R. & Anderson, D. G. Biomaterials for personalized cell therapy. Adv. Mater. 32, 1902005 (2020). This review underscores the importance of biomaterials in tissue regeneration, therapeutic protein delivery and cancer immunotherapy, focusing on advancements in engineering material properties and functionalities tailored for personalized cell therapies.

    Article  Google Scholar 

  168. Keymeulen, B. et al. Encapsulated stem cell-derived β cells exert glucose control in patients with type 1 diabetes. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02055-5 (2023).

  169. Philippidis, A. First patient dosed with VCTX210, a cell therapy for type 1 diabetes: ViaCyte and CRISPR Therapeutics are evaluating an immune-evasive cell replacement therapy that they developed to help patients produce their own insulin. Genet. Eng. Biotechnol. News 42, 10–11 (2022).

    Google Scholar 

  170. Fernandez, E. et al. MVX-ONCO-1 in advanced refractory cancers: Safety, feasibility, and preliminary efficacy results from all HNSCC patients treated in two ongoing clinical trials. J. Clin. Oncol. 39, e18005 (2021).

    Article  Google Scholar 

  171. Mach, N. et al. LBA46 SAKK 11/16, a phase IIa trial evaluating overall survival (OS) for recurrent/metastatic head & neck squamous cell carcinoma (RMHNSCC) patients (pts) progressing after ≥1 line of systemic therapy, treated with MVX-ONCO-1, a novel, first in class cell encapsulation-based immunotherapy. Ann. Oncol. 34, S1286 (2023).

    Article  Google Scholar 

  172. Kauper, K. et al. Continuous intraocular drug delivery lasting over a decade: ciliary neurotrophic factor (CNTF) secreted from Neurotech’s NT-501 implanted in subjects with retinal degenerative disorders. Investig. Ophthalmol. Vis. Sci. 64, 3680–3680 (2023).

    Google Scholar 

  173. Birch, D. G. et al. Randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. Am. J. Ophthalmol. 156, 283–292.e1 (2013).

    Article  Google Scholar 

  174. Chew, E. Y. et al. Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular telangiectasia type 2: a randomized clinical trial. Ophthalmology 126, 540–549 (2019).

    Article  Google Scholar 

  175. Brizuela, C. et al. Cell-based regenerative endodontics for treatment of periapical lesions: a randomized, controlled phase I/II clinical trial. J. Dental Res. 99, 523–529 (2020).

    Article  Google Scholar 

  176. Evans, M. A. et al. Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control. Chem. Sci. 9, 3729–3741 (2018).

    Article  Google Scholar 

  177. Tomás, R. M., Martyn, B., Bailey, T. L. & Gibson, M. I. Engineering cell surfaces by covalent grafting of synthetic polymers to metabolically-labeled glycans. Acs Macro Lett. 7, 1289–1294 (2018).

    Article  Google Scholar 

  178. Zhao, Y. et al. Surface-anchored framework for generating RhD-epitope stealth red blood cells. Sci. Adv. 6, eaaw9679 (2020).

    Article  Google Scholar 

  179. Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022).

    Article  Google Scholar 

  180. Barberio, A. E. et al. Cancer cell coating nanoparticles for optimal tumor-specific cytokine delivery. ACS Nano 14, 11238–11253 (2020).

    Article  Google Scholar 

  181. Wayteck, L. et al. Hitchhiking nanoparticles: reversible coupling of lipid-based nanoparticles to cytotoxic T lymphocytes. Biomaterials 77, 243–254 (2016).

    Article  Google Scholar 

  182. Merivaara, A. et al. Preservation of biomaterials and cells by freeze-drying: change of paradigm. J. Control. Rel. 336, 480–498 (2021).

    Article  Google Scholar 

  183. Wikström, J. et al. Viability of freeze dried microencapsulated human retinal pigment epithelial cells. Eur. J. Pharm. Sci. 47, 520–526 (2012).

    Article  Google Scholar 

  184. Auvinen, V.-V. et al. Effects of nanofibrillated cellulose hydrogels on adipose tissue extract and hepatocellular carcinoma cell spheroids in freeze-drying. Cryobiology 91, 137–145 (2019).

    Article  Google Scholar 

  185. Hamilton, J. R. et al. In vivo human T cell engineering with enveloped delivery vehicles. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02085-z (2024).

  186. Smith, T. T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017).

    Article  Google Scholar 

  187. Breda, L. et al. In vivo hematopoietic stem cell modification by mRNA delivery. Science 381, 436–443 (2023).

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the Leo Foundation and from the John A Paulson School of Engineering & Applied Sciences, Harvard University and Wyss Institute.

Author information

Author notes

  1. Yongsheng Gao

    Present address: Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA

  2. Zhaoqianqi Feng

    Present address: School of Engineering, Westlake University, Hangzhou, Zhejiang, China

Authors and Affiliations

  1. John A. Paulson School of Engineering & Applied Sciences, Harvard University, Allston, MA, USA

    Lily Li-Wen Wang, Yongsheng Gao, Zhaoqianqi Feng, David J. Mooney & Samir Mitragotri

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Lily Li-Wen Wang, David J. Mooney & Samir Mitragotri

Authors
  1. Lily Li-Wen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongsheng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhaoqianqi Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David J. Mooney
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samir Mitragotri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.L.-W.W. and S.M. conceived the article’s concept. L.L.-W.W. collaborated with all authors on the writing. All authors contributed to the article’s research and discussion. Final edits and revisions were done by L.L.-W.W. and S.M. with input from all authors.

Corresponding author

Correspondence to Samir Mitragotri.

Ethics declarations

Competing interests

The authors are inventors of patent applications related to cell therapies. These patents are owned and managed by Harvard University. S.M. declares the following competing interests: Hitch Bio, board member, equity; and Asalyxa, scientific advisory board member, equity. D.J.M. declares the following competing interests: Novartis, sponsored research, licensed intellectual property; Immulus, equity; IVIVA, scientific advisory board member; Attivare, scientific advisory board member, equity; and Lyell, licensed intellectual property, equity.

Peer review

Peer review information

Nature Reviews Bioengineering thanks Liangfang Zhang, Yevgeny Brudno and Yizhou Dong 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.

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

Wang, L.LW., Gao, Y., Feng, Z. et al. Designing drug delivery systems for cell therapy. Nat Rev Bioeng (2024). https://doi.org/10.1038/s44222-024-00214-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s44222-024-00214-0

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