Min Zhang, Shanshan Liang, Meng Wang, Tingfeng Zhang, Jinke Liu, Yuyuan Peng, Fang Hao, Lingna Zheng, Xiao He, Meng Wang, Luling Wu, Tony D. James, Wenkai Zhao, Bing Wang, Weiyue Feng
ABSTRACT Type‐I photodynamic therapy (PDT) agents offer a promising approach for treating hypoxic tumors. However, previous reports mainly focused on thermodynamic modulation through molecular engineering to block the Type‐II energy transfer pathway. Herein, we present a facile strategy to realize the conversion of Type II to Type I PDT by integrating liposomal confinement and electron/hydrogen transfer pathway. A multifunctional nanoplatform, RhM‐R837@Lip was developed, which facilitates an efficient shift from Type II to Type I for hemicyanine‐based photosensitizer (PS) by suppressing singlet oxygen ( 1 O 2 ) generation while promoting superoxide anion (O 2 •− ) and hydroxyl radical (•OH). Lipids serve as electron donors, facilitating electron transfer to form PS radical anions. Additionally, liposomal nanoconfinement acts as a photothermal nanoreactor, achieving a photothermal conversion efficiency as high as 56.1%. Co‐encapsulation of immunoadjuvant R837 stimulates systemic immune responses, synergistically enhancing tumor eradication. This radical‐switching behavior, driven by liposomal nanoconfinement and the donor–π–acceptor (D‐π‐A) structural configuration, modulates electron transfer pathways to favor Type‐I photoreactions. The RhM‐R837@Lip nanoplatform provides a versatile, integrated strategy to overcome hypoxic tumor microenvironments, improving PDT and photocatalytic performance, and effectively inhibits tumor metastasis.