Liposomal Nanoconfinement Enables Type I Photodynamic Conversion for Synergistic Cancer Photothermal-Immunotherapy

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 (¹O₂) generation while promoting superoxide anion (O₂^•−) 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.