Advances in transformable drug delivery systems.

These years, transformable drug delivery systems (DDSs), which hold the capability of changing formulation morphology and subsequent functionality at the desired disease site, have shown great promise in control of spatio-temporal drug delivery/release manner and enhanced treatment efficacy. Equipped with controllability and design flexibility, the transformable DDSs are being increasingly pursued for the development of precision drug delivery platforms for biomedical applications. In this review, we describe the recently developed intracelluarly and extracellularly transformable DDSs, especially associated with assembly or disassociation of the original formulation units, for achieving various functionalities, including prolonged retention time, inhibited endocytosis and enhanced cytotoxicity. Furthermore, the different stimuli, such as pH, enzyme, light, temperature, redox and mechanical force that trigger the transformation process are also introduced. The future outlook and challenges are discussed in the end.

[1]  Alaaldin M. Alkilany,et al.  Gold nanoparticles in biology: beyond toxicity to cellular imaging. , 2008, Accounts of chemical research.

[2]  K. Leong,et al.  Extra- and intra-cellular fate of nanocarriers under dynamic interactions with biology , 2017 .

[3]  P. Gupta,et al.  Hydrogels: from controlled release to pH-responsive drug delivery. , 2002, Drug discovery today.

[4]  Changjun Hou,et al.  Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo , 2015, Nanotechnology.

[5]  Min Jin,et al.  pH-responsive assembly of gold nanoparticles and "spatiotemporally concerted" drug release for synergistic cancer therapy. , 2013, ACS nano.

[6]  Daniel S. Kohane,et al.  External triggering and triggered targeting strategies for drug delivery , 2017 .

[7]  Ming Yan,et al.  Protein nanocapsule weaved with enzymatically degradable polymeric network. , 2009, Nano letters.

[8]  S. Nitti,et al.  Exocytosis of peptide functionalized gold nanoparticles in endothelial cells. , 2012, Nanoscale.

[9]  Younan Xia,et al.  Stimuli‐Responsive Materials for Controlled Release of Theranostic Agents , 2014, Advanced functional materials.

[10]  Zhen Gu,et al.  Stimuli-responsive nanomaterials for therapeutic protein delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[11]  E. Kumacheva,et al.  Rational design for the controlled aggregation of gold nanorods via phospholipid encapsulation for enhanced Raman scattering. , 2014, ACS nano.

[12]  B. Sumerlin,et al.  New directions in thermoresponsive polymers. , 2013, Chemical Society reviews.

[13]  Dalong Ni,et al.  Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy. , 2017, Nature nanotechnology.

[14]  Chad A Mirkin,et al.  Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates , 2013, Proceedings of the National Academy of Sciences.

[15]  M. Welsh,et al.  Reduced Airway Surface pH Impairs Bacterial Killing in the Porcine Cystic Fibrosis Lung , 2012, Nature.

[16]  S. Ganta,et al.  A review of stimuli-responsive nanocarriers for drug and gene delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[17]  L. Brannon-Peppas,et al.  Nanoparticle and targeted systems for cancer therapy. , 2004, Advanced drug delivery reviews.

[18]  Patrick Couvreur,et al.  Stimuli-responsive nanocarriers for drug delivery. , 2013, Nature materials.

[19]  Ying Zhang,et al.  Advanced materials and processing for drug delivery: the past and the future. , 2013, Advanced drug delivery reviews.

[20]  M. C. Stuart,et al.  Emerging applications of stimuli-responsive polymer materials. , 2010, Nature materials.

[21]  M. Sporn,et al.  The tumour microenvironment as a target for chemoprevention , 2007, Nature Reviews Cancer.

[22]  L. Borsig The role of platelet activation in tumor metastasis , 2008, Expert review of anticancer therapy.

[23]  Peng Huang,et al.  Tumor-Specific Formation of Enzyme-Instructed Supramolecular Self-Assemblies as Cancer Theranostics. , 2015, ACS nano.

[24]  G. Thomas,et al.  Furin at the cutting edge: From protein traffic to embryogenesis and disease , 2002, Nature Reviews Molecular Cell Biology.

[25]  Zhen Gu,et al.  Engineering DNA scaffolds for delivery of anticancer therapeutics. , 2015, Biomaterials science.

[26]  Ying Mao,et al.  Guiding Brain‐Tumor Surgery via Blood–Brain‐Barrier‐Permeable Gold Nanoprobes with Acid‐Triggered MRI/SERRS Signals , 2017, Advanced materials.

[27]  Chen-Sheng Yeh,et al.  Near-infrared light-responsive nanomaterials in cancer therapeutics. , 2014, Chemical Society reviews.

[28]  C. Widmann,et al.  Glucose metabolism in cancer cells , 2010, Current opinion in clinical nutrition and metabolic care.

[29]  Zhen Gu,et al.  Engineered Nanoplatelets for Enhanced Treatment of Multiple Myeloma and Thrombus , 2016, Advanced materials.

[30]  Zhen Gu,et al.  Tailoring nanocarriers for intracellular protein delivery. , 2011, Chemical Society reviews.

[31]  Manojit Pramanik,et al.  Light-driven liquid metal nanotransformers for biomedical theranostics , 2017, Nature Communications.

[32]  Andrew L. Ferguson,et al.  Modulation of polypeptide conformation through donor–acceptor transformation of side-chain hydrogen bonding ligands , 2017, Nature Communications.

[33]  Tayyaba Hasan,et al.  Development and applications of photo-triggered theranostic agents. , 2010, Advanced drug delivery reviews.

[34]  Daniel G Anderson,et al.  Injectable nano-network for glucose-mediated insulin delivery. , 2013, ACS nano.

[35]  Zhen Gu,et al.  Tumor microenvironment and intracellular signal-activated nanomaterials for anticancer drug delivery , 2016 .

[36]  Lei Tao,et al.  Redox-responsive polymers for drug delivery: from molecular design to applications , 2014 .

[37]  Quanyin Hu,et al.  Anaerobe-Inspired Anticancer Nanovesicles. , 2017, Angewandte Chemie.

[38]  Guoyao Wu,et al.  Glutathione metabolism and its implications for health. , 2004, The Journal of nutrition.

[39]  Claudiu T. Supuran,et al.  Interfering with pH regulation in tumours as a therapeutic strategy , 2011, Nature Reviews Drug Discovery.

[40]  Zhen Gu,et al.  In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy , 2017, Nature Biomedical Engineering.

[41]  Laurie J. Gay,et al.  Contribution of platelets to tumour metastasis , 2011, Nature Reviews Cancer.

[42]  Zhen Gu,et al.  A novel intracellular protein delivery platform based on single-protein nanocapsules. , 2010, Nature nanotechnology.

[43]  Lisa Brannon-Peppas,et al.  Active targeting schemes for nanoparticle systems in cancer therapeutics. , 2008, Advanced drug delivery reviews.

[44]  Wujin Sun,et al.  Advances in Anticancer Protein Delivery using Micro‐/Nanoparticles , 2014, Particle & particle systems characterization : measurement and description of particle properties and behavior in powders and other disperse systems.

[45]  Mingyuan Gao,et al.  In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics , 2016, Nature Communications.

[46]  F. Alexis,et al.  Stimulus responsive nanogels for drug delivery , 2011 .

[47]  Zhen Gu,et al.  Leveraging Physiology for Precision Drug Delivery , 2017 .

[48]  Quanyin Hu,et al.  Enzyme-responsive nanomaterials for controlled drug delivery. , 2014, Nanoscale.

[49]  Wei Du,et al.  Intracellular Self-Assembly of Taxol Nanoparticles for Overcoming Multidrug Resistance. , 2015, Angewandte Chemie.

[50]  Florian D Jochum,et al.  Temperature- and light-responsive smart polymer materials. , 2013, Chemical Society reviews.

[51]  Jesse V Jokerst,et al.  Molecular imaging with theranostic nanoparticles. , 2011, Accounts of chemical research.

[52]  Bing Xu,et al.  Integrating Enzymatic Self-Assembly and Mitochondria Targeting for Selectively Killing Cancer Cells without Acquired Drug Resistance , 2016, Journal of the American Chemical Society.

[53]  Hua Lu,et al.  Light-responsive helical polypeptides capable of reducing toxicity and unpacking DNA: toward nonviral gene delivery. , 2013, Angewandte Chemie.

[54]  Zaverio M. Ruggeri,et al.  Platelets in atherothrombosis , 2002, Nature Medicine.

[55]  R. Jain,et al.  Delivering nanomedicine to solid tumors , 2010, Nature Reviews Clinical Oncology.

[56]  Ashutosh Chilkoti,et al.  Applications of elastin-like polypeptides in drug delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[57]  H. Hao,et al.  Transformable Nanomaterials as an Artificial Extracellular Matrix for Inhibiting Tumor Invasion and Metastasis. , 2017, ACS nano.

[58]  Lev Dykman,et al.  Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo studies. , 2011, Chemical Society reviews.

[59]  Zhen Gu,et al.  Mechanical Force-Triggered Drug Delivery. , 2016, Chemical reviews.

[60]  Sarah Hurst Petrosko,et al.  Accelerating the Translation of Nanomaterials in Biomedicine. , 2015, ACS nano.

[61]  Miao-Ping Chien,et al.  Enzyme‐Responsive Nanoparticles for Targeted Accumulation and Prolonged Retention in Heart Tissue after Myocardial Infarction , 2015, Advanced materials.

[62]  Zhen Gu,et al.  Clickable protein nanocapsules for targeted delivery of recombinant p53 protein. , 2014, Journal of the American Chemical Society.

[63]  D. Schmaljohann Thermo- and pH-responsive polymers in drug delivery. , 2006, Advanced drug delivery reviews.

[64]  Kinam Park,et al.  Environment-sensitive hydrogels for drug delivery , 2001 .

[65]  Yao-Xin Lin,et al.  General Approach of Stimuli-Induced Aggregation for Monitoring Tumor Therapy. , 2017, ACS nano.

[66]  Zhen Gu,et al.  Transformable liquid-metal nanomedicine , 2015, Nature Communications.

[67]  Rebecca C Taylor,et al.  Apoptosis: controlled demolition at the cellular level , 2008, Nature Reviews Molecular Cell Biology.

[68]  Bing Xu,et al.  Supramolecular catalysis and dynamic assemblies for medicine. , 2017, Chemical Society reviews.

[69]  Warren C W Chan,et al.  The effect of nanoparticle size, shape, and surface chemistry on biological systems. , 2012, Annual review of biomedical engineering.

[70]  V. Torchilin Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery , 2014, Nature Reviews Drug Discovery.

[71]  Z. Werb,et al.  Matrix Metalloproteinases: Regulators of the Tumor Microenvironment , 2010, Cell.

[72]  Yao-Xin Lin,et al.  An in Situ Intracellular Self-Assembly Strategy for Quantitatively and Temporally Monitoring Autophagy. , 2017, ACS nano.

[73]  J. Joyce,et al.  Therapeutic Targeting of the Tumor Microenvironment. , 2021, Cancer discovery.

[74]  Bonnie F. Sloane,et al.  Cysteine cathepsins: multifunctional enzymes in cancer , 2006, Nature Reviews Cancer.

[75]  R. Cardone,et al.  The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis , 2005, Nature Reviews Cancer.

[76]  Leaf Huang,et al.  Pharmacokinetics and biodistribution of nanoparticles. , 2008, Molecular pharmaceutics.

[77]  Quanyin Hu,et al.  Transformable DNA nanocarriers for plasma membrane targeted delivery of cytokine. , 2016, Biomaterials.

[78]  Gang Zheng,et al.  In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging. , 2015, Nature nanotechnology.

[79]  M. Dickey,et al.  Enhanced Endosomal Escape by Light-Fueled Liquid-Metal Transformer. , 2017, Nano letters.

[80]  Arezou A Ghazani,et al.  Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. , 2006, Nano letters.

[81]  Helen Conroy,et al.  Caspase‐activation pathways in apoptosis and immunity , 2003, Immunological reviews.

[82]  T. Cotter,et al.  Apoptosis and cancer: the genesis of a research field , 2009, Nature Reviews Cancer.

[83]  Sheng Dai,et al.  pH-Responsive polymers: synthesis, properties and applications. , 2008, Soft matter.

[84]  E. Holland,et al.  High Precision Imaging of Microscopic Spread of Glioblastoma with a Targeted Ultrasensitive SERRS Molecular Imaging Probe , 2016, Theranostics.

[85]  D. Engelman,et al.  Probe for the measurement of cell surface pH in vivo and ex vivo , 2016, Proceedings of the National Academy of Sciences.

[86]  Jutaek Nam,et al.  pH-Induced aggregation of gold nanoparticles for photothermal cancer therapy. , 2009, Journal of the American Chemical Society.

[87]  Wei Liu,et al.  UV- and NIR-responsive polymeric nanomedicines for on-demand drug delivery , 2013 .

[88]  Bing Xu,et al.  Bioinspired assembly of small molecules in cell milieu. , 2017, Chemical Society reviews.

[89]  Tianyue Jiang,et al.  Tumor Microenvironment-Mediated Construction and Deconstruction of Extracellular Drug-Delivery Depots. , 2016, Nano letters.

[90]  Quanyin Hu,et al.  Relay Drug Delivery for Amplifying Targeting Signal and Enhancing Anticancer Efficacy , 2017, Advanced materials.

[91]  James B. Mitchell,et al.  Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. , 2002, Cancer research.

[92]  Le Tian,et al.  Optical DNA detection based on gold nanorods aggregation. , 2010, Analytica chimica acta.

[93]  T. Mak,et al.  Regulation of cancer cell metabolism , 2011, Nature Reviews Cancer.

[94]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[95]  Timothy J. Foster,et al.  The interaction of bacterial pathogens with platelets , 2006, Nature Reviews Microbiology.

[96]  Zhen Gu,et al.  Stretch-Triggered Drug Delivery from Wearable Elastomer Films Containing Therapeutic Depots. , 2015, ACS nano.

[97]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[98]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[99]  Nathan C. Gianneschi,et al.  Stimuli-Responsive Nanomaterials for Biomedical Applications , 2014, Journal of the American Chemical Society.

[100]  Wei Tao,et al.  Tumor Acidity/NIR Controlled Interaction of Transformable Nanoparticle with Biological Systems for Cancer Therapy. , 2017, Nano letters.

[101]  Yong-Min Huh,et al.  Nanomaterials for theranostics: recent advances and future challenges. , 2015, Chemical reviews.

[102]  J. Liesveld,et al.  Genetic engineering of platelets to neutralize circulating tumor cells. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[103]  Wim E Hennink,et al.  Hydrogels for protein delivery. , 2012, Chemical reviews.

[104]  Mingyuan Gao,et al.  Light‐Triggered Assembly of Gold Nanoparticles for Photothermal Therapy and Photoacoustic Imaging of Tumors In Vivo , 2017, Advanced materials.

[105]  Roger Y Tsien,et al.  Tumor imaging by means of proteolytic activation of cell-penetrating peptides. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[106]  Huile Gao,et al.  Increased Gold Nanoparticle Retention in Brain Tumors by in Situ Enzyme-Induced Aggregation. , 2016, ACS nano.

[107]  Xiaoyuan Chen,et al.  Rethinking cancer nanotheranostics. , 2017, Nature reviews. Materials.

[108]  Daniela A Wilson,et al.  Redox‐Sensitive Stomatocyte Nanomotors: Destruction and Drug Release in the Presence of Glutathione , 2017, Angewandte Chemie.

[109]  Jie Zhou,et al.  In situ generated D-peptidic nanofibrils as multifaceted apoptotic inducers to target cancer cells , 2017, Cell Death & Disease.

[110]  Zhen Gu,et al.  Gel–Liposome‐Mediated Co‐Delivery of Anticancer Membrane‐Associated Proteins and Small‐Molecule Drugs for Enhanced Therapeutic Efficacy , 2014 .

[111]  Ashutosh Chilkoti,et al.  Applications of elastin-like polypeptides in tissue engineering. , 2010, Advanced drug delivery reviews.

[112]  A. Klein-Szanto,et al.  Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[113]  H. Cui,et al.  Tuning Cellular Uptake of Molecular Probes by Rational Design of Their Assembly into Supramolecular Nanoprobes. , 2016, Journal of the American Chemical Society.

[114]  Lei Wang,et al.  Host Materials Transformable in Tumor Microenvironment for Homing Theranostics , 2017, Advanced materials.

[115]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[116]  C. Brennan,et al.  A Brain Tumor Molecular Imaging Strategy Using A New Triple-Modality MRI-Photoacoustic-Raman Nanoparticle , 2011, Nature Medicine.

[117]  Cheng Liu,et al.  Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. , 2003, Cancer research.

[118]  Jie Zheng,et al.  Clearance Pathways and Tumor Targeting of Imaging Nanoparticles. , 2015, ACS nano.

[119]  A. Ashkenazi,et al.  Targeting death and decoy receptors of the tumour-necrosis factor superfamily , 2002, Nature Reviews Cancer.

[120]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[121]  Wujin Sun,et al.  Rolling circle replication for engineering drug delivery carriers. , 2015, Therapeutic delivery.

[122]  Zhen Gu,et al.  Synthetic beta cells for fusion-mediated dynamic insulin secretion. , 2018, Nature chemical biology.

[123]  Hao Wang,et al.  Intracellular construction of topology-controlled polypeptide nanostructures with diverse biological functions , 2017, Nature Communications.

[124]  Zhen Gu,et al.  Cocoon-Like Self-Degradable DNA Nanoclew for Anticancer Drug Delivery , 2014, Journal of the American Chemical Society.