The size of nanocarriers strongly affects their performance in biological systems, especially the capacity to overcome various barriers before delivering the payloads to destinations. However, the optimum size varies at different delivery stages in cancer therapy due to the complicated tumor microenvironment. Relatively large particles are favored for long-term circulation in vivo, while smaller particles contribute to deep penetration into tumor tissues. This dilemma in the size of particles stimulates the development of stimuli-responsive size-shrinking nanocarriers. Herein, we report a facile strategy to construct a tumor-triggered tannic acid (TA) nanoassembly with improved drug delivery efficiency. Cystamine (CA), a small molecule with a disulfide bond, is thus used to mediate TA assembling via cooperative noncovalent interactions, which endows the nanoassembly with intrinsic pH/GSH dual-responsiveness. The obtained TA nanoassemblies were systematically investigated. DOX encapsulated nanoassembly labeled TCFD NP shows high drug loading efficiency, pH/GSH-responsiveness and significant size shrinkage from 122 to 10 nm with simultaneous drug release. The in vitro and in vivo experimental results demonstrate the excellent biocompatibility, sufficient intracellular delivery, enhanced tumor retention/penetration, and superior anticancer efficacy of the small-molecule-mediated nanoassembly. This noncovalent strategy provides a simple method to fabricate a tumor-triggered size-changeable delivery platform to overcome biological barriers.

Acute kidney injury (AKI) is a common and lethal complication for inpatients in the intensive care unit. Accumulative evidence suggests that severe inflammation and oxidative stress are major causes of AKI. Natural polyphenols with potent antioxidative and anti-inflammation activities are promising in the treatment of AKI, but low bioavailability reduces their therapeutic efficacy in vivo. Herein, we reported a novel polyphenol-based nanomedicine comprising a tea polyphenol nanocarrier and the insoluble small-molecule drug curcumin for targeted sepsis-induced AKI therapy. Tea polyphenol nanoparticles (TP-NPs) were synthesized with the tea polyphenol oligomers, and then curcumin-containing nanoparticles (Cur-NPs) were prepared by the loading of curcumin into TP-NPs. In vitro experiments proved the capability of Cur-NPs to scavenge free radicals, protect normal cells from oxidative damage, and suppress the expression of proinflammatory factors. Furthermore, these polyphenol-based nanomedicines effectively alleviated septic AKI by suppressing the inflammation response and restoring oxidant-redox homeostasis in vivo. The prepared Cur-NPs further exhibited carrier-enhanced efficacy due to the therapeutic effects of inornate TP-NPs. In conclusion, the phytochemical nanomedicines provide an attractive strategy for AKI therapy and herald a prospective future in the development of natural reproducible resource-derived nanomedicines for various diseases related to oxidative stress and inflammation.