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New generation of nanomaterials with organelle‐level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria‐targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damage by the synergistic action of oxidative stress and furan‐mediated DNA cross‐linking. Moreover, the phenolic units on PF enable further self‐assembly with Mn2+ via metal‐phenolic coordination to form metal‐phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS‐STING pathway by Mn2+ and tumor‐derived mtDNA in tumor‐associated macrophages (TAMs), and subsequently repolarizing M2‐like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS‐STING‐dependent immunity at the organelle level for potent antitumor efficacy. [ABSTRACT FROM AUTHOR]

Engineering multifunctional nanoplatforms with high therapeutic benefits has become a promising strategy for intractable cancer treatment. A novel polyphenol‐based nanocomplex was designed to evoke highly efficacious cancer immunosurveillance while localizing therapy on the primary tumor and to minimize systemic side effects. This nanocomplex is prepared via metal–polyphenol coordination by encapsulating a natural polyphenol, gossypol, and a newly synthesized polyphenol derivative, polyethylene glycol‐Chlorin e6 (Ce6). The combination of gossypol from cotton and the photosensitizer Ce6 can induce chemotherapeutic/photodynamic immunogenic cancer cell death upon laser irradiation, which is supported by a rich maturation of dendritic cells, concentrated secretion of inflammatory cytokines, and significant inhibition of distant untreated tumors. Finally, an assistance of the programmed‐cell‐death ligand‐1 checkpoint‐blockade immunotherapy can enhance the anti‐tumor immune stimulation of our nanoplatform to a higher level. [ABSTRACT FROM AUTHOR]