Protein-Confined Rotor Strategy for Quantum Yield Enhancement in Supramolecular Photosensitizers toward Sentinel...

Sentinel lymph nodes (SLNs) are pivotal sites for metastatic progression and key indicators of systemic tumor dissemination, with lymphatic metastasis accounting for ∼90% of cancer-related deaths. However, immunotherapy remains largely ineffective, with response rates below 20%, due to the immunosuppressive tumor microenvironment. Here, we present a protein-confined rotor strategy that leverages the supramolecular nanophotosensitizer (BCP3I@M), integrating a Toll-like receptor (TLR7/8) agonist IMDQ and macrophage membrane cloaking for precise SLN targeting. This strategy exploits the protein cavity as a molecular scaffold to constrain the intramolecular motion of the photosensitizer CP, thereby enhancing intersystem crossing efficiency and boosting ¹O₂ generation by 5.6-fold over ICG. As a result, it significantly amplifies photodynamic therapy (PDT)-induced immunogenic cell death, potentiating antigen presentation and immune activation. Comparative evaluation of two treatment paradigms─primary tumor irradiation (NIR Tum.) versus SLN-directed PDT (NIR T-SLN)─revealed the superior efficacy of the latter in suppressing metastatic dissemination and reshaping the SLN immunosuppressive microenvironment. Moreover, selective IMDQ release further promoted antigen presentation and T cell activation, synergistically reinforcing both innate and adaptive immunity. This strategy not only eradicated lung metastases but also extended survival, offering a clinically translatable approach to precision tumor immunotherapy.