‘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.
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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.
Yatvin, M., Weinstein, J., Dennis, W. & Blumenthal, R. Design of liposomes for enhanced local release of drugs by hyperthermia. Science 202, 1290–1293 (1978).
Brownlee, M. & Cerami, A. A glucose-controlled insulin-delivery system: semisynthetic insulin bound to lectin. Science 206, 1190–1191 (1979).
Hoffman, A. S. Stimuli-responsive polymers: biomedical applications and challenges for clinical translation. Adv. Drug Deliv. Rev. 65, 10–16 (2013).
Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).
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).
Purcell, B. P. et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat. Mater. 13, 653–661 (2014).
Traverso, G. & Langer, R. Engineering precision. Sci. Transl. Med. 7, 289ed6 (2015).
Tibbitt, M. W., Dahlman, J. E. & Langer, R. Emerging frontiers in drug delivery. J. Am. Chem. Soc. 138, 704–717 (2016).
Kost, J. & Langer, R. Responsive polymeric delivery systems. Adv. Drug Deliv. Rev. 64, 327–341 (2012).
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.
Wang, S., Huang, P. & Chen, X. Hierarchical targeting strategy for enhanced tumor tissue accumulation/retention and cellular internalization. Adv. Mater. 7340–7364 (2016).
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).
Webber, M. J., Appel, E. A., Meijer, E. W. & Langer, R. Supramolecular biomaterials. Nat. Mater. 15, 13–26 (2016).
Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).
Mo, R. & Gu, Z. Tumor microenvironment and intracellular signal-activated nanomaterials for anticancer drug delivery. Mater. Today 19, 274–283 (2016).
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).
Lu, Y., Sun, W. & Gu, Z. Stimuli-responsive nanomaterials for therapeutic protein delivery. J. Control. Release 194, 1–19 (2014).
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).
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.
Gupta, P., Vermani, K. & Garg, S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov. Today 7, 569–579 (2002).
Hoy, M. R. & Roche, E. J. Taste mask coatings for preparation of chewable pharmaceutical tablets. US patent 5489436 (1996).
Khare, A. R. & Peppas, N. A. Swelling/deswelling of anionic copolymer gels. Biomaterials 16, 559–567 (1995).
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).
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).
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).
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).
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).
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).
Xu, R. et al. An injectable nanoparticle generator enhances delivery of cancer therapeutics. Nat. Biotechnol. 34, 414–418 (2016).
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).
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.
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).
Lee, Y. et al. A protein nanocarrier from charge-conversion polymer in response to endosomal pH. J. Am. Chem. Soc. 129, 5362–5363 (2007).
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.
Sun, W. et al. Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery. J. Am. Chem. Soc. 136, 14722–14725 (2014).
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).
Lu, Y. et al. Transformable liquid-metal nanomedicine. Nat. Commun. 6, 10066 (2015).
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).
Pacardo, D. B., Ligler, F. S. & Gu, Z. Programmable nanomedicine: synergistic and sequential drug delivery systems. Nanoscale 7, 3381–3391 (2015).
Weerakkody, D. et al. Family of pH (low) insertion peptides for tumor targeting. Proc. Natl Acad. Sci. USA 110, 5834–5839 (2013).
Cheng, C. J. et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518, 107–110 (2015).
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).
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).
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).
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).
Slaughter, B. V., Khurshid, S. S., Fisher, O. Z., Khademhosseini, A. & Peppas, N. A. Hydrogels in regenerative medicine. Adv. Mater. 21, 3307–3329 (2009).
You, J.-O. et al. pH-responsive scaffolds generate a pro-healing response. Biomaterials 57, 22–32 (2015).
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).
Kuppusamy, P. et al. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res. 62, 307–312 (2002).
Meng, F., Hennink, W. E. & Zhong, Z. Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30, 2180–2198 (2009).
Zhao, M. et al. Redox-responsive nanocapsules for intracellular protein delivery. Biomaterials 32, 5223–5230 (2011).
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).
Rotruck, J. T. et al. Selenium: biochemical role as a component of glutathione peroxidase. Science 179, 588–590 (1973).
Cao, W., Wang, L. & Xu, H. Selenium/tellurium containing polymer materials in nanobiotechnology. Nano Today 10, 717–736 (2015).
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).
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).
Levine, M. N. & Raines, R. T. Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacology. Chem. Sci. 3, 2412–2420 (2012).
Napoli, A., Valentini, M., Tirelli, N., Muller, M. & Hubbell, J. A. Oxidation-responsive polymeric vesicles. Nat. Mater. 3, 183–189 (2004).
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).
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).
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).
Noh, J. et al. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nat. Commun. 6, 6907 (2015).
Liu, X. et al. Fusogenic reactive oxygen species triggered charge-reversal vector for effective gene delivery. Adv. Mater. 28, 1743–1752 (2016).
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).
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).
Aran, K. et al. Stimuli-responsive electrodes detect oxidative stress and liver injury. Adv. Mater. 27, 1433–1436 (2015).
Overall, C. M. & Kleifeld, O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 6, 227–239 (2006).
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).
Callmann, C. E. et al. Therapeutic enzyme-responsive nanoparticles for targeted delivery and accumulation in tumors. Adv. Mater. 27, 4611–4615 (2015).
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.
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).
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.
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).
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).
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).
Hu, Q. et al. Tumor microenvironment-mediated construction and deconstruction of extracellular drug-delivery depots. Nano Lett. 16, 1118–1126 (2016).
Biswas, A. et al. Endoprotease-mediated intracellular protein delivery using nanocapsules. ACS Nano 5, 1385–1394 (2011).
Jiang, T. et al. Furin-mediated sequential delivery of anticancer cytokine and small-molecule drug shuttled by graphene. Adv. Mater. 27, 1021–1028 (2015).
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).
Gu, Z. et al. Protein nanocapsule weaved with enzymatically degradable polymeric network. Nano Lett. 9, 4533–4538 (2009).
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).
Maitz, M. F. et al. Bio-responsive polymer hydrogels homeostatically regulate blood coagulation. Nat. Commun. 4, 2168 (2013).
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).
Zion, T. C., Zarur, A. & Ying, J. Y. Stimuli-responsive systems for controlled drug delivery. US patent 7531191 (2004).
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).
Matsumoto, A. et al. A synthetic approach toward a self-regulated insulin delivery system. Angew. Chem. Int. Ed. 51, 2124–2128 (2012).
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).
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).
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.
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).
Fischel-Ghodsian, F., Brown, L., Mathiowitz, E., Brandenburg, D. & Langer, R. Enzymatically controlled drug delivery. Proc. Natl Acad. Sci. USA 85, 2403–2406 (1988).
Podual, K., Doyle, F. & Peppas, N. Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase. Polymer 41, 3975–3983 (2000).
Gu, Z. et al. Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. ACS Nano 7, 6758–6766 (2013).
Holtz, J. H. & Asher, S. A. Polymerized colloidal crystal hydrogel films as intelligent chemical sensing materials. Nature 389, 829–832 (1997).
Goldraich, M. & Kost, J. Glucose-sensitive polymeric matrices for controlled drug delivery. Clin. Mater. 13, 135–142 (1993).
Gu, Z. et al. Injectable nano-network for glucose-mediated insulin delivery. ACS Nano 7, 4194–4201 (2013).
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).
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.
Yesilyurt, V. et al. Injectable self-healing glucose-responsive hydrogels with pH-regulated mechanical properties. Adv. Mater. 28, 86–91 (2016).
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).
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).
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).
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).
Shibata, H. et al. Injectable hydrogel microbeads for fluorescence-based in vivo continuous glucose monitoring. Proc. Natl Acad. Sci. USA 107, 17894–17898 (2010).
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).
Seager, H. Drug-delivery products and the Zydis fast-dissolving dosage form. J. Pharm. Pharmacol. 50, 375–382 (1998).
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).
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).
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).
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).
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).
Naito, M. et al. A phenylboronate-functionalized polyion complex micelle for ATP-triggered release of siRNA. Angew. Chem. Int. Ed. 51, 10751–10755 (2012).
Biswas, S. et al. Biomolecular robotics for chemomechanically driven guest delivery fuelled by intracellular ATP. Nat. Chem. 5, 613–620 (2013).
Mo, R., Jiang, T., DiSanto, R., Tai, W. & Gu, Z. ATP-triggered anticancer drug delivery. Nat. Commun. 5, 3364 (2014).
Wu, C. et al. Engineering of switchable aptamer micelle flares for molecular imaging in living cells. ACS Nano 7, 5724–5731 (2013).
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).
Harris, A. L. Hypoxia — a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).
Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11, 393–410 (2011).
Perche, F., Biswas, S., Wang, T., Zhu, L. & Torchilin, V. P. Hypoxia-targeted siRNA delivery. Angew. Chem. Int. Ed. 126, 3430–3434 (2014).
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).
Zheng, X. et al. Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. Nat. Commun. 6, 5834 (2015).
Takasawa, M., Moustafa, R. R. & Baron, J.-C. Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke. Stroke 39, 1629–1637 (2008).
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).
Roy, D., Brooks, W. L. A. & Sumerlin, B. S. New directions in thermoresponsive polymers. Chem. Soc. Rev. 42, 7214–7243 (2013).
Yoshida, R. et al. Comb-type grafted hydrogels with rapid deswelling response to temperature changes. Nature 374, 240–242 (1995).
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).
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.
Wang, C., Flynn, N. T. & Langer, R. Controlled structure and properties of thermoresponsive nanoparticle–hydrogel composites. Adv. Mater. 16, 1074–1079 (2004).
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).
Timko, B. P. et al. Near-infrared–actuated devices for remotely controlled drug delivery. Proc. Natl Acad. Sci. USA 111, 1349–1354 (2014).
Xia, L.-W. et al. Nano-structured smart hydrogels with rapid response and high elasticity. Nat. Commun. 4, 2226 (2013).
Bae, Y. H., Okano, T. & Kim, S. W. Insulin permeation through thermo-sensitive hydrogels. J. Control. Release 9, 271–279 (1989).
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).
Wang, C., Stewart, R. J. & Kopecek, J. Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains. Nature 397, 417–420 (1999).
Meyer, D. E. & Chilkoti, A. Purification of recombinant proteins by fusion with thermally-responsive polypeptides. Nat. Biotechnol. 17, 1112–1115 (1999).
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).
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).
Nettles, D. L., Chilkoti, A. & Setton, L. A. Applications of elastin-like polypeptides in tissue engineering. Adv. Drug Deliv. Rev. 62, 1479–1485 (2010).
Holme, M. N. et al. Shear-stress sensitive lenticular vesicles for targeted drug delivery. Nat. Nanotechnol. 7, 536–543 (2012).
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.
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).
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).
Di, J. et al. Stretch-triggered drug delivery from wearable elastomer films containing therapeutic depots. ACS Nano 9, 9407–9415 (2015).
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).
Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 6, 857–866 (2006).
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).
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).
Wang, Z. et al. Nanoparticle-based artificial RNA silencing machinery for antiviral therapy. Proc. Natl Acad. Sci. USA 109, 12387–12392 (2012).
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.
Kim, Y., Macfarlane, R. J., Jones, M. R. & Mirkin, C. A. Transmutable nanoparticles with reconfigurable surface ligands. Science 351, 579–582 (2016).
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.
Brudno, Y. et al. Refilling drug delivery depots through the blood. Proc. Natl Acad. Sci. USA 111, 12722–12727 (2014).
Rusconi, C. P. et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nat. Biotechnol. 22, 1423–1428 (2004).
Oney, S. et al. Development of universal antidotes to control aptamer activity. Nat. Med. 15, 1224–1228 (2009).
Lee, J. et al. Nucleic acid-binding polymers as anti-inflammatory agents. Proc. Natl Acad. Sci. USA 108, 14055–14060 (2011).
Dvir, T., Timko, B. P., Kohane, D. S. & Langer, R. Nanotechnological strategies for engineering complex tissues. Nat. Nanotechnol. 6, 13–22 (2011).
Rosales, A. M. & Anseth, K. S. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater. 1, 15012 (2016).
Langer, R. & Tirrell, D. A. Designing materials for biology and medicine. Nature 428, 487–492 (2004).
Ulijn, R. V. et al. Bioresponsive hydrogels. Mater. Today 10, 40–48 (2007).
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).
Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).
Pollock, J. F. & Healy, K. E. in Strategies in Regenerative Medicine (ed. Santin, M. ) 1–58 (Springer, 2009).
Koshy, S. T., Ferrante, T. C., Lewin, S. A. & Mooney, D. J. Injectable, porous, and cell-responsive gelatin cryogels. Biomaterials 35, 2477–2487 (2014).
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.
Lutolf, M. P., Raeber, G. P., Zisch, A. H., Tirelli, N. & Hubbell, J. A. Cell-responsive synthetic hydrogels. Adv. Mater. 15, 888–892 (2003).
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).
Annabi, N. et al. Highly elastic and conductive human-based protein hybrid hydrogels. Adv. Mater. 28, 40–49 (2016).
Dvir, T. et al. Nanowired three dimensional cardiac patches. Nat. Nanotechnol. 6, 720–725 (2011).
Shi, D. et al. Photo-cross-linked scaffold with kartogenin-encapsulated nanoparticles for cartilage regeneration. ACS Nano 10, 1292–1299 (2016).
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).
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).
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).
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).
Chen, L. et al. Aptamer-mediated efficient capture and release of T lymphocytes on nanostructured surfaces. Adv. Mater. 23, 4376–4380 (2011).
Zhao, W. et al. Bioinspired multivalent DNA network for capture and release of cells. Proc. Natl Acad. Sci. USA 109, 19626–19631 (2012).
Zhang, P. et al. Programmable fractal nanostructured interfaces for specific recognition and electrochemical release of cancer cells. Adv. Mater. 25, 3566–3570 (2013).
Mosiewicz, K. A. et al. In situ cell manipulation through enzymatic hydrogel photopatterning. Nat. Mater. 12, 1072–1078 (2013).
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).
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.
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).
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.
Clatworthy, A. E., Pierson, E. & Hung, D. T. Targeting virulence: a new paradigm for antimicrobial therapy. Nat. Chem. Biol. 3, 541–548 (2007).
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).
Ning, X. et al. Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat. Mater. 10, 602–607 (2011).
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).
Cabaleiro-Lago, C. et al. Inhibition of amyloid β protein fibrillation by polymeric nanoparticles. J. Am. Chem. Soc. 130, 15437–15443 (2008).
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).
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).
Xiong, M.-H. et al. Bacteria-responsive multifunctional nanogel for targeted antibiotic delivery. Adv. Mater. 24, 6175–6180 (2012).
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).
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).
Traba, C. & Liang, J. F. Bacteria responsive antibacterial surfaces for indwelling device infections. J. Control. Release 198, 18–25 (2015).
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).
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).
Forbes, N. S. Engineering the perfect (bacterial) cancer therapy. Nat. Rev. Cancer 10, 785–794 (2010).
Din, M. O. et al. Synchronized cycles of bacterial lysis for in vivo delivery. Nature 536, 81–85 (2016).
Iverson, N. M. et al. In vivo biosensing via tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes. Nat. Nanotechnol. 8, 873–880 (2013).
Bago, J. R. et al. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat. Commun. 7, 10593 (2016).
Roger, M. et al. Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31, 8393–8401 (2010).
Fang, R. H. et al. Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery. Nano Lett. 14, 2181–2188 (2014).
Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).
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).
Hu, C.-M. J. et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 (2015).
Hu, Q. et al. Anticancer platelet-mimicking nanovehicles. Adv. Mater. 27, 7043–7050 (2015).
Li, J. et al. Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles. Biomaterials 76, 52–65 (2016).
Dou, H. et al. Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery. Blood 108, 2827–2835 (2006).
Kim, H., Cohen, R. E., Hammond, P. T. & Irvine, D. J. Live lymphocyte arrays for biosensing. Adv. Funct. Mater. 16, 1313–1323 (2006).
Huang, B. et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci. Transl. Med. 7, 291ra94(2015).
Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).
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).
Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).
Levine, B. L. & June, C. H. Perspective: assembly line immunotherapy. Nature 498, S17–S17 (2013).
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).
Tong, R. et al. Smart chemistry in polymeric nanomedicine. Chem. Soc. Rev. 43, 6982–7012 (2014).
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).
Mitragotri, S. et al. Accelerating the translation of nanomaterials in biomedicine. ACS Nano 9, 6644–6654 (2015).
Tian, B. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).
Mei, J. et al. Aggregation-induced emission: together we shine, united we soar! Chem. Rev. 115, 11718–11940 (2015).
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).
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).
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.
Ju, C. et al. Sequential intra-intercellular nanoparticle delivery system for deep tumor penetration. Angew. Chem. Int. Ed. 53, 6253–6258 (2014).
Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
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).
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).
Engelmayr, G. C. et al. Accordion-like honeycombs for tissue engineering of cardiac anisotropy. Nat. Mater. 7, 1003–1010 (2008).
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).
Ensign, L. M. et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl. Med. 4, 138ra79 (2012).
Ye, Y. et al. Microneedles integrated with pancreatic cells and synthetic glucose-signal amplifiers for smart insulin delivery. Adv. Mater. 28, 3115–3121 (2016).
Stanley, S. A. et al. Radio-wave heating of iron oxide nanoparticles can regulate plasma glucose in mice. Science 336, 604–608 (2012).
Qian, C. et al. Light-activated hypoxia-responsive nanocarriers for enhanced anticancer therapy. Adv. Mater. 28, 3313–3320 (2016).
Farra, R. et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci. Transl. Med. 4, 122ra21 (2012).
Lee, H. et al. A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy. Nat. Nanotechnol. 11, 566–572 (2016).
Webb, R. C. et al. Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow. Sci. Adv. 1, e1500701 (2015).
Wang, S., Huang, P. & Chen, X. Stimuli-responsive programmed specific targeting in nanomedicine. ACS Nano 10, 2991–2994 (2016).
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).
Schmaljohann, D. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev. 58, 1655–1670 (2006).
Paroutis, P., Touret, N. & Grinstein, S. The pH of the secretory pathway: measurement, determinants, and regulation. Physiology 19, 207–215 (2004).
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).
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).
Bertrand, P. et al. Increased hyaluronidase levels in breast tumor metastases. Int. J. Cancer 73, 327–331 (1997).
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).
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).
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).
Andriole, G. L. et al. Mortality results from a randomized prostate-cancer screening trial. New Engl. J. Med. 360, 1310–1319 (2009).
Schröder, F. H. et al. Screening and prostate-cancer mortality in a randomized European study. New Engl. J. Med. 360, 1320–1328 (2009).
Mo, R., Jiang, T. & Gu, Z. Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery. Angew. Chem. Int. Ed. 126, 5925–5930 (2014).
Höckel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001).
Cheng, C. et al. Large variations in absolute wall shear stress levels within one species and between species. Atherosclerosis 195, 225–235 (2007).
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.).
The authors declare no competing interests.
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Lu, Y., Aimetti, A., Langer, R. et al. Bioresponsive materials. Nat Rev Mater 2, 16075 (2017). https://doi.org/10.1038/natrevmats.2016.75
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