Phthalocyanine Aggregates as “Semiconductor-like” Photocatalysts for Hypoxic-Tumor Photodynamic Immunotherapy

Abstract Photodynamic immunotherapy (PIT) has emerged as a promising approach for efficient eradication of primary tumors and inhibition of tumor metastasis. However, most of photosensitizers (PSs) for PIT exhibit notable oxygen dependence. Herein, a concept emphasizing on transition from molecular PSs into “semiconductor-like” photocatalysts is proposed, which converts the PSs from type II photoreaction to efficient type I photoreaction. Detailed mechanism studies reveal that the nanostructured phthalocyanine aggregate (NanoNMe) generates radical ion pairs through a photoinduced symmetry breaking charge separation process, achieving charge separation through a “self-substrate” approach and leading to exceptional photocatalytic charge transfer activity. Additionally, a reformed phthalocyanine aggregate (NanoNMO) is fabricated to improve the stability in physiological environments. NanoNMO showcases outstanding photocytotoxicities under both normoxic and hypoxic conditions and exhibits remarkable tumor targeting ability. Notably, the photodynamic effect mediated by NanoNMO not only triggers the systemic anti-tumor immune response but also synergizes with PD-1 antibodies to enhance the infiltration of cytotoxic T lymphocytes into tumor sites, leading to the effective inhibition of tumor growth.