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WIREs Nanomed Nanobiotechnol
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Stimuli‐responsive nanotherapeutics for precision drug delivery and cancer therapy

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Cancer remains one of the world's leading causes of death. However, most conventional chemotherapeutic drugs only show a narrow therapeutic window in patients because of their inability to discriminate cancer cells from healthy cells. Nanoparticle‐based therapeutics (termed nanotherapeutics) have emerged as potential solutions to mitigate many obstacles posed by these free drugs. Deep insights into knowledge of the tumor microenvironment and materials science make it possible to construct nanotherapeutics that are able to release cargoes in response to a variety of internal stimuli and external triggers. Therefore, such highly sophisticated nanosystems could help impede the premature release of toxic drugs in the blood circulation or healthy tissues, thus enhancing the safety profiles of encapsulated drugs. In this context, this review offers a comprehensive overview of several specific stimuli, including internal stimuli (e.g., pH, temperature, enzyme, redox, and H2O2) and external stimuli (e.g., magnetic, photo, and ultrasound). We envision that applications of these smart nanotherapeutics can benefit cancer patients and provide a good chance for clinical translation of many nanoparticle formulas. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > in vitro Nanoparticle‐Based Sensing
(a) Passive targeting of nanoparticles. Nanotherapeutics reach tumors selectively through the leaky vasculature surrounding the tumors and the effect of size for retention in the tumor tissue. (b) Active targeting strategies. Nanoparticles are decorated with various ligands that can selectively bind to bioactive molecules overexpressed on the cancer cell surface (Danhier, Feron, & Préat, )
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(a) Schematic illustration of the preparation of PTX‐load and small interfering RNA (siRNA) complexed gas‐cored liposomes. Hetero‐assembly of positively charged siRNA micelles and negatively charged PTX‐loaded gas‐cored liposomes to generate nanoparticles with paclitaxel (PTX) and siRNA encapsulated simultaneously. (b) Schematic diagram of the destruction of nanoparticles when following exposure to an external low‐frequency ultrasound (Yin et al., )
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The controllable release of Ce6 from HAuNS‐pHLIP‐Ce6 nanospheres at a low pH value and near‐infrared (NIR) irradiation (Meng, Fang, Wang, Tan, & Nan, )
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Schematic of one‐step double emulsion method for producing PVA/iron oxide capsules coated with Polyvinyl Alcohol (PVA) polymers
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Schematic illustration of ACMF‐responsive smart nanotherapeutics that generate heat in response to externally applied ACMF and release doxorubicin (DOX) sequentially (Hayashi et al., )
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Schematic representation of the structure of PLGA NPs and intracellular drug release in response to high levels of H2O2 (Chen, He, & Guo, )
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Schematic illustration of DOX‐loaded star‐shaped redox‐responsive micelles. The surface of the micelles is modified with folate ligand to generate cancer cell‐specific nanotherapeutics (star‐PECLss‐FA), and drug release can be triggered by a high intracellular concentration of GSH (Shi et al., )
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Schematic illustration of the structure and function of thermoresponsive and bubble‐generating liposomes. Once accumulated in tumor sites, the encapsulated DOX can be released by heat‐induced CO2 bubbles (Chen et al., )
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Schematic illustration of extracellular matrix (ECM)‐targeting liposomes strengthened by hydrogen bonding. After uptake by cancer cells, the low pH destroys the liposomal structures and triggers the release of the drug payload (Chiang & Lo, )
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Diagnostic Tools > In Vitro Nanoparticle-Based Sensing
Diagnostic Tools > Diagnostic Nanodevices
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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