Abstract

Photodynamic therapy (PDT) is an appealing treatment for oncologic skin diseases owing to its high spatiotemporally selectivity and non-invasive features. However, its application in melanoma has been restricted by limited penetration depth of ultraviolet (UV)-visible (vis) light, melanin-optical filtration and weak immunogenicity. To circumvent the incomplete tumor damage and insufficient anti-tumor immunity, we prepared a mesoporous coated upconverting nanoparticles (NaYF 4 :Yb, [email protected] 4 @mSiO 2 @lipsome)-based platform by co-loading chlorin e6 (Ce6) and buthionine sulfoximine (BSO). This platform converts near-infrared (NIR) light to UV-vis light which enables the destruction of deeply seated nidus, amplification of ferroptotic and apoptotic cell death, as well as an increase in the anti-tumor immunity. Under NIR laser irradiation, NaYF 4 :Yb, [email protected] 4 @mSiO 2 @lipsome nanoparticles embedded with Ce6 were designed to ease burden in tumor sites via elevating levels of hydroxyl radicals and the induction of apoptosis. Meanwhile, glutathione depletion was induced through BSO co-administration and direct thiol oxidation, followed by the inactivation of lipid peroxide repair enzyme and initiation of ferroptosis. This combinational strategy resulted in an amplification in intratumoral oxidative stress, which was accompanied with the strong cytotoxicity in vitro and in vivo . The aggravated anti-tumor performance then brought about the exposure of damage-associated molecular patterns, followed by promoted maturation of dendritic cells and effector function of tumor-infiltrating lymphocytes. Taken together, this ferroptosis-apoptosis combined photodynamic strategy provides insights in designing nanomedicines for immunotherapy in melanoma.