Overcoming chemoresistance via NO-mediated HSP inhibition using hybrid membrane-coated multifunctional nanoplatforms

Chemotherapy resistance and the precise delivery as well as controlled release of drugs at tumor sites remain major challenges in cancer treatment. Heat shock proteins (HSPs) have been identified as key contributors to chemotherapy resistance, yet effective strategies to overcome this issue are still lacking. In this study, we developed a hybrid biomimetic nanoparticle system (CuS-PTX-ICG-L-arg@HR) that integrates photothermal therapy (PTT), chemotherapy, and gas therapy to enhance the efficiency of cervical cancer treatment. By fusing the red blood cell membranes with <i>HeLa cell</i> membranes, the nanoparticles combined immune evasion capabilities with tumortargeting properties, and further improved circulation time and tumor accumulation. To address chemotherapy resistance, we leveraged a novel light-activated nitric oxide (NO) generation strategy, where L-arginine (L-arg) was introduced as a NO precursor to inhibit HSPs expression under near-infrared (NIR) irradiation. To the best of our knowledge, this represents the first attempt to overcome chemotherapy resistance through HSPs inhibition via NO generation, significantly enhancing the efficacy of paclitaxel (PTX) in drug-resistant tumors. Furthermore, the plasmonic properties of hollow copper sulfide (CuS) nanoparticles enable light-triggered drug release and localized therapeutic effects, ensuring precise tumor targeting and reducing off-target toxicity. This multifunctional nanoplatform offers a promising strategy for improving drug delivery, reversing chemotherapy resistance and advancing precision cancer therapy.