Cascade-Amplifying Immunophototherapy Nanoplatform Integrating Cocktail Drug Delivery.

Abstract

Photodynamic therapy (PDT) offers the advantages of non-invasiveness, non-drug resistance, and high selectivity. However, its efficacy against melanoma is substantially limited by tumor hypoxia, elevated glutathione levels, and the strong antioxidant and light-absorbing properties of melanin. Herein, we developed a cascade-amplified biomimetic nanoplatform (Cyan-Cu) by assembling cyanobacteria (Cyan) and DSPE-PEG-NH2-decorated copper (II) phthalocyanine (CuPc) for enhanced melanoma therapy. Under 635 nm laser irradiation, the Cyan-Cu not only simultaneously generates both reactive oxygen species and heat for immunophototherapy, but also functions as a cocktail drug delivery system. In contrast to conventional microalgae used merely as photosynthetic oxygen generator or delivery vector, the Cyan effectively suppresses tyrosinase activity, thereby limiting the synthesis of antioxidant melanin and significantly potentiating both PDT and cuproptosis. Notably, the photothermal effect cascades to trigger Cyan disintegration into small cytotoxic fragments, enabling deeper tumor penetration for amplified anti-tumor efficacy. In vivo studies demonstrated that the Cyan-Cu platform reduced intratumoral melanin content while suppressing bilateral tumor growth via dual-mode immune activation. This work underscores the pivotal role of Cyan in antimelanoma therapy and illustrates the therapeutic potential of the Cyan-Cu platform as a multimodal synergistic strategy.