Suppressing Reverse Intersystem Crossing by Confining Organic Molecules within LDH Interlayers for Near‐Infrared‐II Photodynamic Immunotherapy

Photodynamic therapy (PDT) leveraging near-infrared-II (NIR-II) light holds promise for deep-tissue cancer treatment, yet conventional photosensitizers (PSs) suffer from low singlet oxygen (¹O₂) quantum yields due to inefficient intersystem crossing (ISC) and short-lived triplet states, hindering PDT effectiveness and subsequent immunogenic cell death (ICD) induction. Herein, a dual-optimized PS is reported by intercalating I-functionalized isophthalic acid (I-IPA) into ZnAl-LDH interlayers (LDH@I-IPA) for NIR-II PDT/immunotherapy. LDH-mediated confinement effect not only narrows the bandgap for effective NIR-II excitation, but also prolongs its triplet lifetime by 3 orders of magnitude through suppressing reverse intersystem crossing (RISC). Combined with I-induced heavy-atom effect promoting ISC, LDH@I-IPA achieves a record-high relative ¹O₂ quantum yield of 1.89. After polyethylene glycol (PEG) modification, LDH@I-IPA-PEG demonstrates potent tumor apoptosis and ICD, suppressing primary/metastatic tumors by 99.5%/52.2% through dendritic cell maturation, macrophage polarization, and cytotoxic T-cell activation. Theoretical calculations and transcriptomic analysis confirm bandgap engineering, RISC inhibition, and immune pathway regulation.