Near-Infrared Light-Controlled Nitric Oxide Delivery Combined with In Situ Activated Chemotherapy for Enhanced Multimodal Therapy

Development of nanoplatforms with in situ activation for chemotherapy represents a promising modality for biomedical application. Herein, a multifunctional nanoplatform, CMS@DTC@PDA@RuNO@FA (abbreviated as CDPNF NPs), was developed for highly efficient antitumor therapy, in which diethyldithiocarbamate (DTC)-loaded mesoporous Cu₂MoS₄ (CMS) nanoparticles were covered by polydopamine (PDA) layers and further covalently modified with a NO donor (RuNO) and a folic acid (FA)-directing moiety. Under the mild acidic tumor microenvironment (TME), the CDPNF NPs co-liberated DTC and Cu²⁺ in the tumor site, where in situ formation of the highly cytotoxic Cu(DTC)₂ complex effectively killed tumor cells. Furthermore, under near-infrared (NIR) light irradiation, the CDPNF NPs could deliver nitric oxide (NO) and produce superoxide anions (O₂^•-), followed by the formation of more toxic peroxynitrite (ONOO^-), which led to promoted cell apoptosis. Under 1064 nm NIR light irradiation, in vivo experiments with CDPNF NPs demonstrated an impressively high tumor inhibition rate (∼97%) while with good biocompatibility. This work represents an in situ activated approach for precision medicine that might imply its promising potential for clinical applications.