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:

Bioresponsive materials

Abstract

‘Smart’ bioresponsive materials that are sensitive to biological signals or to pathological abnormalities, and interact with or are actuated by them, are appealing therapeutic platforms for the development of next-generation precision medications. Armed with a better understanding of various biologically responsive mechanisms, researchers have made innovations in the areas of materials chemistry, biomolecular engineering, pharmaceutical science, and micro- and nanofabrication to develop bioresponsive materials for a range of applications, including controlled drug delivery, diagnostics, tissue engineering and biomedical devices. This Review highlights recent advances in the design of smart materials capable of responding to the physiological environment, to biomarkers and to biological particulates. Key design principles, challenges and future directions, including clinical translation, of bioresponsive materials are also discussed.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Typical physiological environments with associated biological stimuli.
Figure 2: Materials sensitive to biological particulates.
Figure 3: General design rationale of bioresponsive materials.

Similar content being viewed by others

References

  1. Langer, R. & Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797–800 (1976). A pioneering study of the use of engineered materials for controlled drug delivery.

    Article  CAS  Google Scholar 

  2. Yatvin, M., Weinstein, J., Dennis, W. & Blumenthal, R. Design of liposomes for enhanced local release of drugs by hyperthermia. Science 202, 1290–1293 (1978).

    Article  CAS  Google Scholar 

  3. Brownlee, M. & Cerami, A. A glucose-controlled insulin-delivery system: semisynthetic insulin bound to lectin. Science 206, 1190–1191 (1979).

    Article  CAS  Google Scholar 

  4. Hoffman, A. S. Stimuli-responsive polymers: biomedical applications and challenges for clinical translation. Adv. Drug Deliv. Rev. 65, 10–16 (2013).

    Article  CAS  Google Scholar 

  5. Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).

    Article  CAS  Google Scholar 

  6. Caldorera-Moore, M. E., Liechty, W. B. & Peppas, N. A. Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers. Acc. Chem. Res. 44, 1061–1070 (2011).

    Article  CAS  Google Scholar 

  7. Purcell, B. P. et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat. Mater. 13, 653–661 (2014).

    Article  CAS  Google Scholar 

  8. Traverso, G. & Langer, R. Engineering precision. Sci. Transl. Med. 7, 289ed6 (2015).

    Article  Google Scholar 

  9. Tibbitt, M. W., Dahlman, J. E. & Langer, R. Emerging frontiers in drug delivery. J. Am. Chem. Soc. 138, 704–717 (2016).

    Article  CAS  Google Scholar 

  10. Kost, J. & Langer, R. Responsive polymeric delivery systems. Adv. Drug Deliv. Rev. 64, 327–341 (2012).

    Article  Google Scholar 

  11. Mitragotri, S., Burke, P. A. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13, 655–672 (2014). A noteworthy review of current formulations and delivery strategies for overcoming challenges in biomolecule administration.

    Article  CAS  Google Scholar 

  12. Wang, S., Huang, P. & Chen, X. Hierarchical targeting strategy for enhanced tumor tissue accumulation/retention and cellular internalization. Adv. Mater. 7340–7364 (2016).

  13. Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived β cells in immune-competent mice. Nat. Med. 22, 306–311 (2016).

    Article  CAS  Google Scholar 

  14. Webber, M. J., Appel, E. A., Meijer, E. W. & Langer, R. Supramolecular biomaterials. Nat. Mater. 15, 13–26 (2016).

    Article  CAS  Google Scholar 

  15. Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).

    Article  CAS  Google Scholar 

  16. Mo, R. & Gu, Z. Tumor microenvironment and intracellular signal-activated nanomaterials for anticancer drug delivery. Mater. Today 19, 274–283 (2016).

    Article  CAS  Google Scholar 

  17. Veiseh, O., Tang, B. C., Whitehead, K. A., Anderson, D. G. & Langer, R. Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug Discov. 14, 45–57 (2015).

    Article  CAS  Google Scholar 

  18. Lu, Y., Sun, W. & Gu, Z. Stimuli-responsive nanomaterials for therapeutic protein delivery. J. Control. Release 194, 1–19 (2014).

    Article  CAS  Google Scholar 

  19. Apostolovic, B., Danial, M. & Klok, H.-A. Coiled coils: attractive protein folding motifs for the fabrication of self-assembled, responsive and bioactive materials. Chem. Soc. Rev. 39, 3541–3575 (2010).

    Article  CAS  Google Scholar 

  20. Lowman, A., Morishita, M., Kajita, M., Nagai, T. & Peppas, N. Oral delivery of insulin using pH-responsive complexation gels. J. Pharm. Sci. 88, 933–937 (1999). A pH-responsive hydrogel that can protect orally delivered insulin from digestion in the stomach, but swell at neutral and basic environments for insulin release.

  21. Gupta, P., Vermani, K. & Garg, S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov. Today 7, 569–579 (2002).

    Article  CAS  Google Scholar 

  22. Hoy, M. R. & Roche, E. J. Taste mask coatings for preparation of chewable pharmaceutical tablets. US patent 5489436 (1996).

  23. Khare, A. R. & Peppas, N. A. Swelling/deswelling of anionic copolymer gels. Biomaterials 16, 559–567 (1995).

    Article  CAS  Google Scholar 

  24. Koetting, M. C., Guido, J. F., Gupta, M., Zhang, A. & Peppas, N. A. pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. J. Control. Release 221, 18–25 (2016).

    Article  CAS  Google Scholar 

  25. Ling, D. et al. Multifunctional tumor pH-Sensitive self-assembled nanoparticles for bimodal imaging and treatment of resistant heterogeneous tumors. J. Am. Chem. Soc. 136, 5647–5655 (2014).

    Article  CAS  Google Scholar 

  26. Boussif, O. et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl Acad. Sci. USA 92, 7297–7301 (1995).

    Article  CAS  Google Scholar 

  27. Anderson, D. G., Lynn, D. M. & Langer, R. Semi-automated synthesis and screening of a large library of degradable cationic polymers for gene delivery. Angew. Chem. Int. Ed. 115, 3261–3266 (2003).

    Article  Google Scholar 

  28. Murthy, N., Thng, Y. X., Schuck, S., Xu, M. C. & Fréchet, J. M. J. A. Novel strategy for encapsulation and release of proteins: hydrogels and microgels with acid-labile acetal cross-linkers. J. Am. Chem. Soc. 124, 12398–12399 (2002).

    Article  CAS  Google Scholar 

  29. Parrott, M. C. et al. Tunable bifunctional silyl ether cross-linkers for the design of acid-sensitive biomaterials. J. Am. Chem. Soc. 132, 17928–17932 (2010).

    Article  CAS  Google Scholar 

  30. Xu, R. et al. An injectable nanoparticle generator enhances delivery of cancer therapeutics. Nat. Biotechnol. 34, 414–418 (2016).

    Article  CAS  Google Scholar 

  31. Kabanov, A. V., Bronich, T. K., Kabanov, V. A., Yu, K. & Eisenberg, A. Soluble stoichiometric complexes from poly(N-ethyl-4-vinylpyridinium) cations and poly(ethylene oxide)-block-polymethacrylate anions. Macromolecules 29, 6797–6802 (1996).

    Article  CAS  Google Scholar 

  32. Harada, A. & Kataoka, K. Formation of polyion complex micelles in an aqueous milieu from a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments. Macromolecules 28, 5294–5299 (1995). Original demonstration of polyion complex micelles, which represent a family of pH-responsive nanoformulations.

    Article  CAS  Google Scholar 

  33. Bae, Y., Fukushima, S., Harada, A. & Kataoka, K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Ed. 42, 4640–4643 (2003).

    Article  CAS  Google Scholar 

  34. Lee, Y. et al. A protein nanocarrier from charge-conversion polymer in response to endosomal pH. J. Am. Chem. Soc. 129, 5362–5363 (2007).

    Article  CAS  Google Scholar 

  35. Hartgerink, J. D., Beniash, E. & Stupp, S. I. Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 294, 1684–1688 (2001). pH-triggered assembly of peptide-amphiphiles into nanofibres.

    Article  CAS  Google Scholar 

  36. Sun, W. et al. Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery. J. Am. Chem. Soc. 136, 14722–14725 (2014).

    Article  CAS  Google Scholar 

  37. Rim, H. P., Min, K. H., Lee, H. J., Jeong, S. Y. & Lee, S. C. pH-Tunable calcium phosphate covered mesoporous silica nanocontainers for intracellular controlled release of guest drugs. Angew. Chem. Int. Ed. 50, 8853–8857 (2011).

    Article  CAS  Google Scholar 

  38. Lu, Y. et al. Transformable liquid-metal nanomedicine. Nat. Commun. 6, 10066 (2015).

    Article  CAS  Google Scholar 

  39. Mi, P. et al. A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat. Nanotechnol. 11, 724–730 (2016).

    Article  CAS  Google Scholar 

  40. Pacardo, D. B., Ligler, F. S. & Gu, Z. Programmable nanomedicine: synergistic and sequential drug delivery systems. Nanoscale 7, 3381–3391 (2015).

    Article  CAS  Google Scholar 

  41. Weerakkody, D. et al. Family of pH (low) insertion peptides for tumor targeting. Proc. Natl Acad. Sci. USA 110, 5834–5839 (2013).

    Article  CAS  Google Scholar 

  42. Cheng, C. J. et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518, 107–110 (2015).

    Article  CAS  Google Scholar 

  43. Wang, Y. et al. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat. Mater. 13, 204–212 (2014).

    Article  CAS  Google Scholar 

  44. Li, H.-J. et al. Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy. Proc. Natl Acad. Sci. USA 113, 4164–4169 (2016).

    Article  CAS  Google Scholar 

  45. Garbern, J. C., Minami, E., Stayton, P. S. & Murry, C. E. Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium. Biomaterials 32, 2407–2416 (2011).

    Article  CAS  Google Scholar 

  46. Zhang, S. et al. A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices. Nat. Mater. 14, 1065–1071 (2015).

    Article  CAS  Google Scholar 

  47. Slaughter, B. V., Khurshid, S. S., Fisher, O. Z., Khademhosseini, A. & Peppas, N. A. Hydrogels in regenerative medicine. Adv. Mater. 21, 3307–3329 (2009).

    Article  CAS  Google Scholar 

  48. You, J.-O. et al. pH-responsive scaffolds generate a pro-healing response. Biomaterials 57, 22–32 (2015).

    Article  CAS  Google Scholar 

  49. Wu, G., Fang, Y.-Z., Yang, S., Lupton, J. R. & Turner, N. D. Glutathione metabolism and its implications for health. J. Nutr. 134, 489–492 (2004).

    Article  CAS  Google Scholar 

  50. Kuppusamy, P. et al. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res. 62, 307–312 (2002).

    CAS  Google Scholar 

  51. Meng, F., Hennink, W. E. & Zhong, Z. Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30, 2180–2198 (2009).

    Article  CAS  Google Scholar 

  52. Zhao, M. et al. Redox-responsive nanocapsules for intracellular protein delivery. Biomaterials 32, 5223–5230 (2011).

    Article  CAS  Google Scholar 

  53. Miyata, K. et al. Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression. J. Am. Chem. Soc. 126, 2355–2361 (2004).

    Article  CAS  Google Scholar 

  54. Rotruck, J. T. et al. Selenium: biochemical role as a component of glutathione peroxidase. Science 179, 588–590 (1973).

    Article  CAS  Google Scholar 

  55. Cao, W., Wang, L. & Xu, H. Selenium/tellurium containing polymer materials in nanobiotechnology. Nano Today 10, 717–736 (2015).

    Article  CAS  Google Scholar 

  56. Ma, N., Li, Y., Xu, H., Wang, Z. & Zhang, X. Dual redox responsive assemblies formed from diselenide block copolymers. J. Am. Chem. Soc. 132, 442–443 (2010).

    Article  CAS  Google Scholar 

  57. Yang, J., Liu, W., Sui, M., Tang, J. & Shen, Y. Platinum (iv)-coordinate polymers as intracellular reduction-responsive backbone-type conjugates for cancer drug delivery. Biomaterials 32, 9136–9143 (2011).

    Article  CAS  Google Scholar 

  58. Levine, M. N. & Raines, R. T. Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacology. Chem. Sci. 3, 2412–2420 (2012).

    Article  CAS  Google Scholar 

  59. Napoli, A., Valentini, M., Tirelli, N., Muller, M. & Hubbell, J. A. Oxidation-responsive polymeric vesicles. Nat. Mater. 3, 183–189 (2004).

    Article  CAS  Google Scholar 

  60. Shim, M. S. & Xia, Y. A. Reactive oxygen species (ROS)-responsive polymer for safe, efficient, and targeted gene delivery in cancer cells. Angew. Chem. Int. Ed. 52, 6926–6929 (2013).

    Article  CAS  Google Scholar 

  61. Ma, Y., Dong, W.-F., Hempenius, M. A., Mohwald, H. & Julius Vancso, G. Redox-controlled molecular permeability of composite-wall microcapsules. Nat. Mater. 5, 724–729 (2006).

    Article  CAS  Google Scholar 

  62. Broaders, K. E., Grandhe, S. & Fréchet, J. M. J. A. Biocompatible oxidation-triggered carrier polymer with potential in therapeutics. J. Am. Chem. Soc. 133, 756–758 (2011).

    Article  CAS  Google Scholar 

  63. Noh, J. et al. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nat. Commun. 6, 6907 (2015).

    Article  CAS  Google Scholar 

  64. Liu, X. et al. Fusogenic reactive oxygen species triggered charge-reversal vector for effective gene delivery. Adv. Mater. 28, 1743–1752 (2016).

    Article  CAS  Google Scholar 

  65. Wang, M., Sun, S., Neufeld, C. I., Perez-Ramirez, B. & Xu, Q. Reactive oxygen species-responsive protein modification and its intracellular delivery for targeted cancer therapy. Angew. Chem. Int. Ed. 53, 13444–13448 (2014).

    Article  CAS  Google Scholar 

  66. Chung, M.-F., Chia, W.-T., Wan, W.-L., Lin, Y.-J. & Sung, H.-W. Controlled release of an anti-inflammatory drug using an ultrasensitive ROS-responsive gas-generating carrier for localized inflammation inhibition. J. Am. Chem. Soc. 137, 12462–12465 (2015).

    Article  CAS  Google Scholar 

  67. Aran, K. et al. Stimuli-responsive electrodes detect oxidative stress and liver injury. Adv. Mater. 27, 1433–1436 (2015).

    Article  CAS  Google Scholar 

  68. Overall, C. M. & Kleifeld, O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 6, 227–239 (2006).

    Article  CAS  Google Scholar 

  69. Olson, E. S. et al. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proc. Natl Acad. Sci. USA 107, 4311–4316 (2010).

    Article  Google Scholar 

  70. Callmann, C. E. et al. Therapeutic enzyme-responsive nanoparticles for targeted delivery and accumulation in tumors. Adv. Mater. 27, 4611–4615 (2015).

    Article  CAS  Google Scholar 

  71. Jiang, T. et al. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc. Natl Acad. Sci. USA 101, 17867–17872 (2004). Demonstration of a generic tumour targeting strategy based on protease-activatable cell-penetrating peptides.

    Article  CAS  Google Scholar 

  72. Nguyen, Q. T. et al. Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. Proc. Natl Acad. Sci. USA 107, 4317–4322 (2010).

    Article  CAS  Google Scholar 

  73. Zhang, S. et al. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease. Sci. Transl. Med. 7, 300ra128 (2015). An inflammation-responsive hydrogel for triggered drug delivery toward inflammatory bowel disease.

    Article  CAS  Google Scholar 

  74. Gajanayake, T. et al. A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft. Sci. Transl. Med. 6, 249ra110 (2014).

    Article  CAS  Google Scholar 

  75. Kim, H.-J., Zhang, K., Moore, L. & Ho, D. Diamond nanogel-embedded contact lenses mediate lysozyme-dependent therapeutic release. ACS Nano 8, 2998–3005 (2014).

    Article  CAS  Google Scholar 

  76. Jiang, T., Mo, R., Bellotti, A., Zhou, J. & Gu, Z. Gel–liposome-mediated co-delivery of anticancer membrane-associated proteins and small-molecule drugs for enhanced therapeutic efficacy. Adv. Funct. Mater. 24, 2295–2304 (2014).

    Article  CAS  Google Scholar 

  77. Hu, Q. et al. Tumor microenvironment-mediated construction and deconstruction of extracellular drug-delivery depots. Nano Lett. 16, 1118–1126 (2016).

    Article  CAS  Google Scholar 

  78. Biswas, A. et al. Endoprotease-mediated intracellular protein delivery using nanocapsules. ACS Nano 5, 1385–1394 (2011).

    Article  CAS  Google Scholar 

  79. Jiang, T. et al. Furin-mediated sequential delivery of anticancer cytokine and small-molecule drug shuttled by graphene. Adv. Mater. 27, 1021–1028 (2015).

    Article  CAS  Google Scholar 

  80. Kang, J.-H. et al. Design of polymeric carriers for cancer-specific gene targeting: utilization of abnormal protein kinase Cα activation in cancer cells. J. Am. Chem. Soc. 130, 14906–14907 (2008).

    Article  CAS  Google Scholar 

  81. Gu, Z. et al. Protein nanocapsule weaved with enzymatically degradable polymeric network. Nano Lett. 9, 4533–4538 (2009).

    Article  CAS  Google Scholar 

  82. Linderoth, L., Peters, G. H., Madsen, R. & Andresen, T. L. Drug delivery by an enzyme-mediated cyclization of a lipid prodrug with unique bilayer-formation properties. Angew. Chem. Int. Ed. 48, 1823–1826 (2009).

    Article  CAS  Google Scholar 

  83. Maitz, M. F. et al. Bio-responsive polymer hydrogels homeostatically regulate blood coagulation. Nat. Commun. 4, 2168 (2013).

    Article  CAS  Google Scholar 

  84. Mo, R., Jiang, T., Di, J., Tai, W. & Gu, Z. Emerging micro- and nanotechnology based synthetic approaches for insulin delivery. Chem. Soc. Rev. 43, 3595–3629 (2014).

    Article  CAS  Google Scholar 

  85. Zion, T. C., Zarur, A. & Ying, J. Y. Stimuli-responsive systems for controlled drug delivery. US patent 7531191 (2004).

  86. Pai, C. M., Bae, Y. H., Mack, E. J., Wilson, D. E. & Kim, S. W. Concanavalin A microspheres for a self-regulating insulin delivery system. J. Pharm. Sci. 81, 532–536 (1992).

    Article  CAS  Google Scholar 

  87. Matsumoto, A. et al. A synthetic approach toward a self-regulated insulin delivery system. Angew. Chem. Int. Ed. 51, 2124–2128 (2012).

    Article  CAS  Google Scholar 

  88. Makino, K., Mack, E. J., Okano, T. & Kim, S. W. A microcapsule self-regulating delivery system for insulin. J. Control. Release 12, 235–239 (1990).

    Article  CAS  Google Scholar 

  89. Podual, K., Doyle, F. J. & Peppas, N. A. Glucose-sensitivity of glucose oxidase-containing cationic copolymer hydrogels having poly (ethylene glycol) grafts. J. Control. Release 67, 9–17 (2000).

    Article  CAS  Google Scholar 

  90. Chou, D. H.-C. et al. Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates. Proc. Natl Acad. Sci. USA 112, 2401–2406 (2015). In vivo demonstration of a glucose-responsive insulin derivative chemically modified with PBA.

    Article  CAS  Google Scholar 

  91. Kim, H., Kang, Y. J., Kang, S. & Kim, K. T. Monosaccharide-responsive release of insulin from polymersomes of polyboroxole block copolymers at neutral pH. J. Am. Chem. Soc. 134, 4030–4033 (2012).

    Article  CAS  Google Scholar 

  92. Fischel-Ghodsian, F., Brown, L., Mathiowitz, E., Brandenburg, D. & Langer, R. Enzymatically controlled drug delivery. Proc. Natl Acad. Sci. USA 85, 2403–2406 (1988).

    Article  CAS  Google Scholar 

  93. Podual, K., Doyle, F. & Peppas, N. Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase. Polymer 41, 3975–3983 (2000).

    Article  CAS  Google Scholar 

  94. Gu, Z. et al. Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. ACS Nano 7, 6758–6766 (2013).

    Article  CAS  Google Scholar 

  95. Holtz, J. H. & Asher, S. A. Polymerized colloidal crystal hydrogel films as intelligent chemical sensing materials. Nature 389, 829–832 (1997).

    Article  CAS  Google Scholar 

  96. Goldraich, M. & Kost, J. Glucose-sensitive polymeric matrices for controlled drug delivery. Clin. Mater. 13, 135–142 (1993).

    Article  CAS  Google Scholar 

  97. Gu, Z. et al. Injectable nano-network for glucose-mediated insulin delivery. ACS Nano 7, 4194–4201 (2013).

    Article  CAS  Google Scholar 

  98. Podual, K., Doyle, F. J. III & Peppas, N. A. Dynamic behavior of glucose oxidase-containing microparticles of poly (ethylene glycol)-grafted cationic hydrogels in an environment of changing pH. Biomaterials 21, 1439–1450 (2000).

    Article  CAS  Google Scholar 

  99. Yu, J. et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl Acad. Sci. USA 112, 8260–8265 (2015). Demonstration of a bioresponsive microneedle-array patch for smart insulin delivery.

    Article  CAS  Google Scholar 

  100. Yesilyurt, V. et al. Injectable self-healing glucose-responsive hydrogels with pH-regulated mechanical properties. Adv. Mater. 28, 86–91 (2016).

    Article  CAS  Google Scholar 

  101. Liu, H. et al. Dual-responsive surfaces modified with phenylboronic acid-containing polymer brush to reversibly capture and release cancer cells. J. Am. Chem. Soc. 135, 7603–7609 (2013).

    Article  CAS  Google Scholar 

  102. Wang, C., Ye, Y., Hochu, G. M., Sadeghifar, H. & Gu, Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody. Nano Lett. 16, 2334–2340 (2016).

    Article  CAS  Google Scholar 

  103. Barone, P. W. & Strano, M. S. Reversible control of carbon nanotube aggregation for a glucose affinity sensor. Angew. Chem. Int. Ed. 45, 8138–8141 (2006).

    Article  CAS  Google Scholar 

  104. Yum, K. et al. Boronic acid library for selective, reversible near-infrared fluorescence quenching of surfactant suspended single-walled carbon nanotubes in response to glucose. ACS Nano 6, 819–830 (2012).

    Article  CAS  Google Scholar 

  105. Shibata, H. et al. Injectable hydrogel microbeads for fluorescence-based in vivo continuous glucose monitoring. Proc. Natl Acad. Sci. USA 107, 17894–17898 (2010).

    Article  Google Scholar 

  106. Yoshida, T., Lai, T. C., Kwon, G. S. & Sako, K. pH- and ion-sensitive polymers for drug delivery. Expert Opin. Drug Deliv. 10, 1497–1513 (2013).

    Article  CAS  Google Scholar 

  107. Seager, H. Drug-delivery products and the Zydis fast-dissolving dosage form. J. Pharm. Pharmacol. 50, 375–382 (1998).

    Article  CAS  Google Scholar 

  108. Bodmeier, R., Guo, X., Sarabia, R. E. & Skultety, P. F. The influence of buffer species and strength on diltiazem HC1 release from beads coated with the aqueous cationic polymer dispersions, eudragit RS, RL 30D. Pharm. Res. 13, 52–56 (1996).

    Article  CAS  Google Scholar 

  109. Du, H., Wickramasinghe, R. & Qian, X. Effects of salt on the lower critical solution temperature of poly (N-isopropylacrylamide). J. Phys. Chem. B 114, 16594–16604 (2010).

    Article  CAS  Google Scholar 

  110. Harada, A. & Kataoka, K. On–off control of enzymatic activity synchronizing with reversible formation of supramolecular assembly from enzyme and charged block copolymers. J. Am. Chem. Soc. 121, 9241–9242 (1999).

    Article  CAS  Google Scholar 

  111. Nakamura, T., Takashima, Y., Hashidzume, A., Yamaguchi, H. & Harada, A. A metal–ion-responsive adhesive material via switching of molecular recognition properties. Nat. Commun. 5, 4622 (2014).

    Article  CAS  Google Scholar 

  112. Lao, Y.-H., Phua, K. K. L. & Leong, K. W. Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation. ACS Nano 9, 2235–2254 (2015).

    Article  CAS  Google Scholar 

  113. Naito, M. et al. A phenylboronate-functionalized polyion complex micelle for ATP-triggered release of siRNA. Angew. Chem. Int. Ed. 51, 10751–10755 (2012).

    Article  CAS  Google Scholar 

  114. Biswas, S. et al. Biomolecular robotics for chemomechanically driven guest delivery fuelled by intracellular ATP. Nat. Chem. 5, 613–620 (2013).

    Article  CAS  Google Scholar 

  115. Mo, R., Jiang, T., DiSanto, R., Tai, W. & Gu, Z. ATP-triggered anticancer drug delivery. Nat. Commun. 5, 3364 (2014).

    Article  CAS  Google Scholar 

  116. Wu, C. et al. Engineering of switchable aptamer micelle flares for molecular imaging in living cells. ACS Nano 7, 5724–5731 (2013).

    Article  CAS  Google Scholar 

  117. Zhang, P. et al. Near infrared-guided smart nanocarriers for MicroRNA-controlled release of doxorubicin/siRNA with intracellular ATP as fuel. ACS Nano 10, 3637–3647 (2016).

    Article  CAS  Google Scholar 

  118. Harris, A. L. Hypoxia — a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    Article  CAS  Google Scholar 

  119. Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11, 393–410 (2011).

    Article  CAS  Google Scholar 

  120. Perche, F., Biswas, S., Wang, T., Zhu, L. & Torchilin, V. P. Hypoxia-targeted siRNA delivery. Angew. Chem. Int. Ed. 126, 3430–3434 (2014).

    Article  Google Scholar 

  121. Zhang, G., Palmer, G. M., Dewhirst, M. W. & Fraser, C. L. A dual-emissive-materials design concept enables tumour hypoxia imaging. Nat. Mater. 8, 747–751 (2009).

    Article  CAS  Google Scholar 

  122. Zheng, X. et al. Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. Nat. Commun. 6, 5834 (2015).

    Article  CAS  Google Scholar 

  123. Takasawa, M., Moustafa, R. R. & Baron, J.-C. Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke. Stroke 39, 1629–1637 (2008).

    Article  CAS  Google Scholar 

  124. Kiyose, K. et al. Hypoxia-sensitive fluorescent probes for in vivo real-time fluorescence imaging of acute ischemia. J. Am. Chem. Soc. 132, 15846–15848 (2010).

    Article  CAS  Google Scholar 

  125. Roy, D., Brooks, W. L. A. & Sumerlin, B. S. New directions in thermoresponsive polymers. Chem. Soc. Rev. 42, 7214–7243 (2013).

    Article  CAS  Google Scholar 

  126. Yoshida, R. et al. Comb-type grafted hydrogels with rapid deswelling response to temperature changes. Nature 374, 240–242 (1995).

    Article  CAS  Google Scholar 

  127. Huffman, A. S., Afrassiabi, A. & Dong, L. C. Thermally reversible hydrogels: II. Delivery and selective removal of substances from aqueous solutions. J. Control. Release 4, 213–222 (1986).

    Article  Google Scholar 

  128. Bae, Y. H., Okano, T., Hsu, R. & Kim, S. W. Thermo-sensitive polymers as on–off switches for drug release. Makromol. Chem. Rapid Commun. 8, 481–485 (1987). Use of thermoresponsive copolymer for pulsatile drug release.

    Article  CAS  Google Scholar 

  129. Wang, C., Flynn, N. T. & Langer, R. Controlled structure and properties of thermoresponsive nanoparticle–hydrogel composites. Adv. Mater. 16, 1074–1079 (2004).

    Article  CAS  Google Scholar 

  130. O'Neal, D. P., Hirsch, L. R., Halas, N. J., Payne, J. D. & West, J. L. Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles. Cancer Lett. 209, 171–176 (2004).

    Article  CAS  Google Scholar 

  131. Timko, B. P. et al. Near-infrared–actuated devices for remotely controlled drug delivery. Proc. Natl Acad. Sci. USA 111, 1349–1354 (2014).

    Article  CAS  Google Scholar 

  132. Xia, L.-W. et al. Nano-structured smart hydrogels with rapid response and high elasticity. Nat. Commun. 4, 2226 (2013).

    Article  CAS  Google Scholar 

  133. Bae, Y. H., Okano, T. & Kim, S. W. Insulin permeation through thermo-sensitive hydrogels. J. Control. Release 9, 271–279 (1989).

    Article  CAS  Google Scholar 

  134. Okano, T., Bae, Y. H., Jacobs, H. & Kim, S. W. Thermally on–off switching polymers for drug permeation and release. J. Control. Release 11, 255–265 (1990).

    Article  CAS  Google Scholar 

  135. Wang, C., Stewart, R. J. & Kopecek, J. Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains. Nature 397, 417–420 (1999).

    Article  CAS  Google Scholar 

  136. Meyer, D. E. & Chilkoti, A. Purification of recombinant proteins by fusion with thermally-responsive polypeptides. Nat. Biotechnol. 17, 1112–1115 (1999).

    Article  CAS  Google Scholar 

  137. McDaniel, J. R., Callahan, D. J. & Chilkoti, A. Drug delivery to solid tumors by elastin-like polypeptides. Adv. Drug Deliv. Rev. 62, 1456–1467 (2010).

    Article  CAS  Google Scholar 

  138. Amiram, M., Luginbuhl, K. M., Li, X., Feinglos, M. N. & Chilkoti, A. Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. Proc. Natl Acad. Sci. USA 110, 2792–2797 (2013).

    Article  Google Scholar 

  139. Nettles, D. L., Chilkoti, A. & Setton, L. A. Applications of elastin-like polypeptides in tissue engineering. Adv. Drug Deliv. Rev. 62, 1479–1485 (2010).

    Article  CAS  Google Scholar 

  140. Holme, M. N. et al. Shear-stress sensitive lenticular vesicles for targeted drug delivery. Nat. Nanotechnol. 7, 536–543 (2012).

    Article  CAS  Google Scholar 

  141. Korin, N. et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 337, 738–742 (2012). Use of a shear-sensitive micro-aggregate for targeting diseased blood vessels with obstruction.

    Article  CAS  Google Scholar 

  142. 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).

    CAS  Google Scholar 

  143. Suzuki, M., Hori, K., Abe, I., Saito, S. & Sato, H. A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II. J. Natl Cancer Inst. 67, 663–669 (1981).

    CAS  Google Scholar 

  144. Di, J. et al. Stretch-triggered drug delivery from wearable elastomer films containing therapeutic depots. ACS Nano 9, 9407–9415 (2015).

    Article  CAS  Google Scholar 

  145. Laulicht, B., Traverso, G., Deshpande, V., Langer, R. & Karp, J. M. Simple battery armor to protect against gastrointestinal injury from accidental ingestion. Proc. Natl Acad. Sci. USA 111, 16490–16495 (2014).

    Article  CAS  Google Scholar 

  146. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 6, 857–866 (2006).

    Article  CAS  Google Scholar 

  147. Zhang, P. et al. In situ amplification of intracellular MicroRNA with MNAzyme nanodevices for multiplexed imaging, logic operation, and controlled drug release. ACS Nano 9, 789–798 (2015).

    Article  CAS  Google Scholar 

  148. Zhang, P. et al. DNA-hybrid-gated multifunctional mesoporous silica nanocarriers for dual-targeted and MicroRNA-responsive controlled drug delivery. Angew. Chem. Int. Ed. 53, 2371–2375 (2014).

    Article  CAS  Google Scholar 

  149. Wang, Z. et al. Nanoparticle-based artificial RNA silencing machinery for antiviral therapy. Proc. Natl Acad. Sci. USA 109, 12387–12392 (2012).

    Article  Google Scholar 

  150. Mirkin, C. A., Letsinger, R. L., Mucic, R. C. & Storhoff, J. J. A. DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 382, 607–609 (1996). A DNA-based approach for the rational and reversible assembly of gold nanoparticles.

    Article  CAS  Google Scholar 

  151. Kim, Y., Macfarlane, R. J., Jones, M. R. & Mirkin, C. A. Transmutable nanoparticles with reconfigurable surface ligands. Science 351, 579–582 (2016).

    Article  CAS  Google Scholar 

  152. Ohta, S., Glancy, D. & Chan, W. C. W. DNA-controlled dynamic colloidal nanoparticle systems for mediating cellular interaction. Science 351, 841–845 (2016). Use of DNA to regulate particle–cell interactions.

  153. Brudno, Y. et al. Refilling drug delivery depots through the blood. Proc. Natl Acad. Sci. USA 111, 12722–12727 (2014).

    Article  CAS  Google Scholar 

  154. Rusconi, C. P. et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nat. Biotechnol. 22, 1423–1428 (2004).

    Article  CAS  Google Scholar 

  155. Oney, S. et al. Development of universal antidotes to control aptamer activity. Nat. Med. 15, 1224–1228 (2009).

    Article  CAS  Google Scholar 

  156. Lee, J. et al. Nucleic acid-binding polymers as anti-inflammatory agents. Proc. Natl Acad. Sci. USA 108, 14055–14060 (2011).

    Article  Google Scholar 

  157. Dvir, T., Timko, B. P., Kohane, D. S. & Langer, R. Nanotechnological strategies for engineering complex tissues. Nat. Nanotechnol. 6, 13–22 (2011).

    Article  CAS  Google Scholar 

  158. Rosales, A. M. & Anseth, K. S. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater. 1, 15012 (2016).

    Article  CAS  Google Scholar 

  159. Langer, R. & Tirrell, D. A. Designing materials for biology and medicine. Nature 428, 487–492 (2004).

    Article  CAS  Google Scholar 

  160. Ulijn, R. V. et al. Bioresponsive hydrogels. Mater. Today 10, 40–48 (2007).

    Article  CAS  Google Scholar 

  161. Wang, H., Tibbitt, M. W., Langer, S. J., Leinwand, L. A. & Anseth, K. S. Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway. Proc. Natl Acad. Sci. USA 110, 19336–19341 (2013).

    Article  CAS  Google Scholar 

  162. Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).

    Article  CAS  Google Scholar 

  163. Pollock, J. F. & Healy, K. E. in Strategies in Regenerative Medicine (ed. Santin, M. ) 1–58 (Springer, 2009).

    Book  Google Scholar 

  164. Koshy, S. T., Ferrante, T. C., Lewin, S. A. & Mooney, D. J. Injectable, porous, and cell-responsive gelatin cryogels. Biomaterials 35, 2477–2487 (2014).

    Article  CAS  Google Scholar 

  165. Lutolf, M. et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc. Natl Acad. Sci. USA 100, 5413–5418 (2003). Demonstration of MMP-responsive synthetic hydrogels to imitate natural MMP-mediated invasion.

    Article  CAS  Google Scholar 

  166. Lutolf, M. P., Raeber, G. P., Zisch, A. H., Tirelli, N. & Hubbell, J. A. Cell-responsive synthetic hydrogels. Adv. Mater. 15, 888–892 (2003).

    Article  CAS  Google Scholar 

  167. Kraehenbuehl, T. P., Ferreira, L. S., Zammaretti, P., Hubbell, J. A. & Langer, R. Cell-responsive hydrogel for encapsulation of vascular cells. Biomaterials 30, 4318–4324 (2009).

    Article  CAS  Google Scholar 

  168. Annabi, N. et al. Highly elastic and conductive human-based protein hybrid hydrogels. Adv. Mater. 28, 40–49 (2016).

    Article  CAS  Google Scholar 

  169. Dvir, T. et al. Nanowired three dimensional cardiac patches. Nat. Nanotechnol. 6, 720–725 (2011).

    Article  CAS  Google Scholar 

  170. Shi, D. et al. Photo-cross-linked scaffold with kartogenin-encapsulated nanoparticles for cartilage regeneration. ACS Nano 10, 1292–1299 (2016).

    Article  CAS  Google Scholar 

  171. Griffin, D. R., Weaver, W. M., Scumpia, P. O., Di Carlo, D. & Segura, T. Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat. Mater. 14, 737–744 (2015).

    Article  CAS  Google Scholar 

  172. Zhang, Z., Chen, N., Li, S., Battig, M. R. & Wang, Y. Programmable hydrogels for controlled cell catch and release using hybridized aptamers and complementary sequences. J. Am. Chem. Soc. 134, 15716–15719 (2012).

    Article  CAS  Google Scholar 

  173. Vermesh, U. et al. High-density, multiplexed patterning of cells at single-cell resolution for tissue engineering and other applications. Angew. Chem. Int. Ed. 50, 7378–7380 (2011).

    Article  CAS  Google Scholar 

  174. Benoit, D. S. W., Schwartz, M. P., Durney, A. R. & Anseth, K. S. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat. Mater. 7, 816–823 (2008).

    Article  CAS  Google Scholar 

  175. Chen, L. et al. Aptamer-mediated efficient capture and release of T lymphocytes on nanostructured surfaces. Adv. Mater. 23, 4376–4380 (2011).

    Article  CAS  Google Scholar 

  176. Zhao, W. et al. Bioinspired multivalent DNA network for capture and release of cells. Proc. Natl Acad. Sci. USA 109, 19626–19631 (2012).

    Article  Google Scholar 

  177. Zhang, P. et al. Programmable fractal nanostructured interfaces for specific recognition and electrochemical release of cancer cells. Adv. Mater. 25, 3566–3570 (2013).

    Article  CAS  Google Scholar 

  178. Mosiewicz, K. A. et al. In situ cell manipulation through enzymatic hydrogel photopatterning. Nat. Mater. 12, 1072–1078 (2013).

    Article  CAS  Google Scholar 

  179. DeForest, C. A. & Tirrell, D. A. A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels. Nat. Mater. 14, 523–531 (2015).

    Article  CAS  Google Scholar 

  180. Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59–63 (2009). Precise control of cellular activity over the hydrogel by light irradiation.

    Article  CAS  Google Scholar 

  181. DeForest, C. A. & Anseth, K. S. Cytocompatible click-based hydrogels with dynamically tunable properties through orthogonal photoconjugation and photocleavage reactions. Nat. Chem. 3, 925–931 (2011).

    Article  CAS  Google Scholar 

  182. Gu, L. & Mooney, D. J. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat. Rev. Cancer 16, 56–66 (2016). This perspective provides insights into anticancer strategies based on engineering the tumour microenvironment.

    Article  CAS  Google Scholar 

  183. Clatworthy, A. E., Pierson, E. & Hung, D. T. Targeting virulence: a new paradigm for antimicrobial therapy. Nat. Chem. Biol. 3, 541–548 (2007).

    Article  CAS  Google Scholar 

  184. Li, Y., Liu, G., Wang, X., Hu, J. & Liu, S. Enzyme-responsive polymeric vesicles for bacterial-strain-selective delivery of antimicrobial agents. Angew. Chem. Int. Ed. 128, 1792–1796 (2016).

    Article  Google Scholar 

  185. Ning, X. et al. Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat. Mater. 10, 602–607 (2011).

    Article  CAS  Google Scholar 

  186. Verma, A., Nakade, H., Simard, J. M. & Rotello, V. M. Recognition and stabilization of peptide α-helices using templatable nanoparticle receptors. J. Am. Chem. Soc. 126, 10806–10807 (2004).

    Article  CAS  Google Scholar 

  187. Cabaleiro-Lago, C. et al. Inhibition of amyloid β protein fibrillation by polymeric nanoparticles. J. Am. Chem. Soc. 130, 15437–15443 (2008).

    Article  CAS  Google Scholar 

  188. Hoshino, Y. et al. Recognition, neutralization, and clearance of target peptides in the bloodstream of living mice by molecularly imprinted polymer nanoparticles: a plastic antibody. J. Am. Chem. Soc. 132, 6644–6645 (2010).

    Article  CAS  Google Scholar 

  189. Lee, M.-R., Baek, K.-H., Jin, H. J., Jung, Y.-G. & Shin, I. Targeted enzyme-responsive drug carriers: studies on the delivery of a combination of drugs. Angew. Chem. Int. Ed. 43, 1675–1678 (2004).

    Article  CAS  Google Scholar 

  190. Xiong, M.-H. et al. Bacteria-responsive multifunctional nanogel for targeted antibiotic delivery. Adv. Mater. 24, 6175–6180 (2012).

    Article  CAS  Google Scholar 

  191. Komnatnyy, V. V., Chiang, W.-C., Tolker-Nielsen, T., Givskov, M. & Nielsen, T. E. Bacteria-triggered release of antimicrobial agents. Angew. Chem. Int. Ed. 53, 439–441 (2014).

    Article  CAS  Google Scholar 

  192. Radovic-Moreno, A. F. et al. Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics. ACS Nano 6, 4279–4287 (2012).

    Article  CAS  Google Scholar 

  193. Traba, C. & Liang, J. F. Bacteria responsive antibacterial surfaces for indwelling device infections. J. Control. Release 198, 18–25 (2015).

    Article  CAS  Google Scholar 

  194. Yoo, J.-W., Irvine, D. J., Discher, D. E. & Mitragotri, S. Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat. Rev. Drug Discov. 10, 521–535 (2011).

    Article  CAS  Google Scholar 

  195. Mohamadzadeh, M., Duong, T., Sandwick, S. J., Hoover, T. & Klaenhammer, T. R. Dendritic cell targeting of Bacillus anthracis protective antigen expressed by Lactobacillus acidophilus protects mice from lethal challenge. Proc. Natl Acad. Sci. USA 106, 4331–4336 (2009).

    Article  Google Scholar 

  196. Forbes, N. S. Engineering the perfect (bacterial) cancer therapy. Nat. Rev. Cancer 10, 785–794 (2010).

    Article  CAS  Google Scholar 

  197. Din, M. O. et al. Synchronized cycles of bacterial lysis for in vivo delivery. Nature 536, 81–85 (2016).

    Article  CAS  Google Scholar 

  198. Iverson, N. M. et al. In vivo biosensing via tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes. Nat. Nanotechnol. 8, 873–880 (2013).

    Article  CAS  Google Scholar 

  199. Bago, J. R. et al. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat. Commun. 7, 10593 (2016).

    Article  CAS  Google Scholar 

  200. Roger, M. et al. Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31, 8393–8401 (2010).

    Article  CAS  Google Scholar 

  201. Fang, R. H. et al. Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery. Nano Lett. 14, 2181–2188 (2014).

    Article  CAS  Google Scholar 

  202. Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).

    Article  CAS  Google Scholar 

  203. Hu, C.-M. J., Fang, R. H., Copp, J., Luk, B. T. & Zhang, L. A biomimetic nanosponge that absorbs pore-forming toxins. Nat. Nanotechnol. 8, 336–340 (2013).

    Article  CAS  Google Scholar 

  204. Hu, C.-M. J. et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 (2015).

    Article  CAS  Google Scholar 

  205. Hu, Q. et al. Anticancer platelet-mimicking nanovehicles. Adv. Mater. 27, 7043–7050 (2015).

    Article  CAS  Google Scholar 

  206. Li, J. et al. Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles. Biomaterials 76, 52–65 (2016).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  208. Kim, H., Cohen, R. E., Hammond, P. T. & Irvine, D. J. Live lymphocyte arrays for biosensing. Adv. Funct. Mater. 16, 1313–1323 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  210. Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    Article  CAS  Google Scholar 

  211. 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  CAS  Google Scholar 

  212. Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).

    Article  CAS  Google Scholar 

  213. Levine, B. L. & June, C. H. Perspective: assembly line immunotherapy. Nature 498, S17–S17 (2013).

    Article  CAS  Google Scholar 

  214. Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc. Natl Acad. Sci. USA 90, 720–724 (1993).

    Article  CAS  Google Scholar 

  215. Tong, R. et al. Smart chemistry in polymeric nanomedicine. Chem. Soc. Rev. 43, 6982–7012 (2014).

    Article  CAS  Google Scholar 

  216. Svenson, S., Wolfgang, M., Hwang, J., Ryan, J. & Eliasof, S. Preclinical to clinical development of the novel camptothecin nanopharmaceutical CRLX101. J. Control. Release 153, 49–55 (2011).

    Article  CAS  Google Scholar 

  217. Mitragotri, S. et al. Accelerating the translation of nanomaterials in biomedicine. ACS Nano 9, 6644–6654 (2015).

    Article  CAS  Google Scholar 

  218. Tian, B. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).

    Article  CAS  Google Scholar 

  219. Mei, J. et al. Aggregation-induced emission: together we shine, united we soar! Chem. Rev. 115, 11718–11940 (2015).

    Article  CAS  Google Scholar 

  220. Cheng, R., Meng, F., Deng, C., Klok, H.-A. & Zhong, Z. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34, 3647–3657 (2013).

    Article  CAS  Google Scholar 

  221. Peppas, N. A. Historical perspective on advanced drug delivery: how engineering design and mathematical modeling helped the field mature. Adv. Drug Deliv. Rev. 65, 5–9 (2013).

    Article  CAS  Google Scholar 

  222. Ma, M., Guo, L., Anderson, D. G. & Langer, R. Bio-inspired polymer composite actuator and generator driven by water gradients. Science 339, 186–189 (2013). Description of a water-responsive film that could contract and expand in response to the surrounding environment, such as skin moisture.

    Article  CAS  Google Scholar 

  223. Ju, C. et al. Sequential intra-intercellular nanoparticle delivery system for deep tumor penetration. Angew. Chem. Int. Ed. 53, 6253–6258 (2014).

    Article  CAS  Google Scholar 

  224. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  Google Scholar 

  225. Cho, W. K. et al. Microstructured barbs on the North American porcupine quill enable easy tissue penetration and difficult removal. Proc. Natl Acad. Sci. USA 109, 21289–21294 (2012).

    Article  Google Scholar 

  226. Merkel, T. J. et al. Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles. Proc. Natl Acad. Sci. USA 108, 586–591 (2011).

    Article  Google Scholar 

  227. Engelmayr, G. C. et al. Accordion-like honeycombs for tissue engineering of cardiac anisotropy. Nat. Mater. 7, 1003–1010 (2008).

    Article  CAS  Google Scholar 

  228. Anselmo, A. C. et al. Platelet-like nanoparticles: mimicking shape, flexibility, and surface biology of platelets to target vascular injuries. ACS Nano 8, 11243–11253 (2014).

    Article  CAS  Google Scholar 

  229. Ensign, L. M. et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl. Med. 4, 138ra79 (2012).

    Article  Google Scholar 

  230. 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  CAS  Google Scholar 

  231. Stanley, S. A. et al. Radio-wave heating of iron oxide nanoparticles can regulate plasma glucose in mice. Science 336, 604–608 (2012).

    Article  CAS  Google Scholar 

  232. Qian, C. et al. Light-activated hypoxia-responsive nanocarriers for enhanced anticancer therapy. Adv. Mater. 28, 3313–3320 (2016).

    Article  CAS  Google Scholar 

  233. Farra, R. et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci. Transl. Med. 4, 122ra21 (2012).

    Article  CAS  Google Scholar 

  234. Lee, H. et al. A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy. Nat. Nanotechnol. 11, 566–572 (2016).

    Article  CAS  Google Scholar 

  235. Webb, R. C. et al. Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow. Sci. Adv. 1, e1500701 (2015).

    Article  CAS  Google Scholar 

  236. Wang, S., Huang, P. & Chen, X. Stimuli-responsive programmed specific targeting in nanomedicine. ACS Nano 10, 2991–2994 (2016).

    Article  CAS  Google Scholar 

  237. Steen, K. H., Steen, A. E. & Reeh, P. W. A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin in vitro. J. Neurosci. 15, 3982–3989 (1995).

    Article  CAS  Google Scholar 

  238. Schmaljohann, D. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev. 58, 1655–1670 (2006).

    Article  CAS  Google Scholar 

  239. Paroutis, P., Touret, N. & Grinstein, S. The pH of the secretory pathway: measurement, determinants, and regulation. Physiology 19, 207–215 (2004).

    Article  CAS  Google Scholar 

  240. Iizasa, T. et al. Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. Clin. Cancer Res. 5, 149–153 (1999).

    CAS  Google Scholar 

  241. Parks, W. C., Wilson, C. L. & Lopez-Boado, Y. S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617–629 (2004).

    Article  CAS  Google Scholar 

  242. Bertrand, P. et al. Increased hyaluronidase levels in breast tumor metastases. Int. J. Cancer 73, 327–331 (1997).

    Article  CAS  Google Scholar 

  243. Lokeshwar, V. B., Lokeshwar, B. L., Pham, H. T. & Block, N. L. Association of elevated levels of hyaluronidase, a matrix-degrading enzyme, with prostate cancer progression. Cancer Res. 56, 651–657 (1996).

    CAS  Google Scholar 

  244. Pham, H. T., Block, N. L. & Lokeshwar, V. B. Tumor-derived hyaluronidase: a diagnostic urine marker for high-grade bladder cancer. Cancer Res. 57, 778–783 (1997).

    CAS  Google Scholar 

  245. Boekholdt, S. M. et al. Serum levels of type II secretory phospholipase A2 and the risk of future coronary artery disease in apparently healthy men and women. The EPIC-Norfolk Prospective Population Study. Arterioscler. Thromb. Vasc. Biol. 25, 839–846 (2005).

    Article  CAS  Google Scholar 

  246. Andriole, G. L. et al. Mortality results from a randomized prostate-cancer screening trial. New Engl. J. Med. 360, 1310–1319 (2009).

    Article  CAS  Google Scholar 

  247. Schröder, F. H. et al. Screening and prostate-cancer mortality in a randomized European study. New Engl. J. Med. 360, 1320–1328 (2009).

    Article  Google Scholar 

  248. Mo, R., Jiang, T. & Gu, Z. Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery. Angew. Chem. Int. Ed. 126, 5925–5930 (2014).

    Article  Google Scholar 

  249. Höckel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001).

    Article  Google Scholar 

  250. Cheng, C. et al. Large variations in absolute wall shear stress levels within one species and between species. Atherosclerosis 195, 225–235 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NC TraCS, the Clinical and Translational Science Awards (CTSA, 1UL1TR001111) of the US National Institutes of Health (NIH) at University of North Carolina at Chapel Hill, Grants 1-14-JF-29 and 1-15-ACE-21 from the American Diabetes Association, and Sloan Research Fellowship (to Z.G.), as well as NIH Grants EB016101-01A1 and EB006365 (to R.L.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Robert Langer or Zhen Gu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Supplementary information S1 (Table)

Summary of typical bio-responsive chemical structures (PDF 3400 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, Y., Aimetti, A., Langer, R. et al. Bioresponsive materials. Nat Rev Mater 2, 16075 (2017). https://doi.org/10.1038/natrevmats.2016.75

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/natrevmats.2016.75

This article is cited by

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