Hyaluronic acid-camouflaged dendritic silica nanoparticles enable targeted cuproptosis and photothermal therapy for lung cancer.

Cuproptosis, has attracted increasing attention in cancer therapy due to its apoptosis-independent mechanism and potential to overcome drug resistance. However, current copper-mediated nanotherapeutics are still limited by low drug-loading efficiency and insufficient therapeutic versatility. Herein, a tumor microenvironment-responsive nanoplatform, HA-SiO2@ESCu-Hemin (SNECHA), was developed for combined cuproptosis-photothermal therapy. Dendritic SiO2 nanoparticles were sequentially loaded with elesclomol-copper complex (ESCu) and hemin, followed by hyaluronic acid (HA) coating to achieve CD44-mediated tumor targeting and HAase/pH-responsive drug release. After internalization, ESCu induced cuproptosis through FDX1-mediated copper reduction, Fe-S cluster disruption, and DLAT-associated proteotoxic stress, while hemin enabled 808 nm laser-triggered photothermal therapy. SNECHA showed efficient near-infrared photothermal conversion with an efficiency of 46.69% and increased to 57.3 °C. In addition, it exhibited enhanced cellular uptake, selective cytotoxicity toward A549 cells with IC50 value of 103.2 nM under laser illumination, and significantly improved antitumor efficacy. In vivo results further demonstrated enhanced tumor accumulation, superior tumor growth inhibition, and favorable preliminary biosafety. This work provides a targeted nanotherapeutic strategy for enhanced cancer treatment through cuproptosis-photothermal combination therapy.