Mitochondrial targeted melanin@mSiO2 yolk-shell nanostructures for NIR-Ⅱ-driven photo-thermal-dynamic/immunotherapy

• The AIPH@MS-CTPP yolk-shell nanostructure was successfully constructed. • The large mesopores can significantly increase the loading amount of AIPH. • NIR-Ⅱ mediated PTT and TDT has higher tissue penetration depth. • Natural melanin nanoparticles can repolarize M2 TAMs to antitumor M1 phenotype. The challenge of photothermal therapy (PTT) clinical transformation is the limited penetration depth of laser light and the general concern of using synthetic photothermal nanomaterials. Hence, it is of great significance to develop combined cancer therapies based on NIR-II photothermal agents from natural materials. Herein, natural melanin nanoparticles from cuttlefish ink coated with large pore mesoporous SiO 2 were developed to load azodiisobutylimidazoline hydrochloride (AIPH@MS). After modification with (3-carboxypropyl) triphenylphosphonium bromide (CTPP), AIPH@MS-CTPP nanoparticles showed enhanced retention in the tumor site and were further delivered to thermally susceptible mitochondria. Under 1064 nm laser irradiation, hyperthermia produced by melanin not only directly leads to cell death but also promotes AIPH release to generate oxygen-independent alkyl free radicals, which could further attack tumor cells. The collaboration of the photothermal effect of melanin and thermodynamic therapy of AIPH could induce a local antitumor immune response and effectively reprogram tumor-associated macrophages from the M2 to M1 phenotype. In combination with anti-PD-1 immune checkpoint blockade, the paralyzed immune system was awakened to inhibit and eliminate secondary metastatic tumors. The NIR-II-driven treatment in this paper can achieve energy conversion processes from NIR-II light to thermal energy and then to chemical energy to perform photothermal-dynamic therapy and immunotherapy. This will overcome the high side effects and insufficient antitumor immune response of PTT and provide a strategy for effective and mild antitumor therapy with clinically approved laser power and safe nanotechnology.