Protein-Confined Rotor Strategy for Quantum Yield Enhancement in Supramolecular Photosensitizers toward Sentinel Lymph Node-Targeted Photodynamic Immunoactivation

Abstract

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.