Molecular Engineering of Quinolinium Cyanine Nanoagonist for Metastasis-Suppressed NIR-II Photothermal Immunotherapy.

Abstract

Despite the therapeutic promise of photothermal immunotherapy in triple-negative breast cancer (TNBC), engineering second near-infrared (NIR-II) window-responsive organic immunophotothermal agents persists as a critical hurdle. We address this gap by designing a molecularly tailored NIR-II photothermal sensitizer (BOQCyCN), which concurrently enables tumor-localized hyperthermia and systemic immunomodulation for combinatorial tumor clearance. Rational structure manipulation through benzyl donor-cyano acceptor functionalization on a 4-methylquinoline core induces a redshifted absorption maximum (λ_max = 1022 nm), achieving deep-tissue penetration within the NIR-II biological therapeutic window. Co-assembly with DSPE-mPEG2000 generates stable BOQCyCN nanoparticles (NPs) exhibiting ultrahigh photothermal conversion (PCE, η = 62.9%) and irradiation resistance. At low irradiance (1064 nm, 0.6 W cm^- ²), NPs initiate synergistic therapeutic cascades: (1) Primary tumor ablation (95% volume reduction) with amplified T-cell infiltration (CD8⁺: 5.5-fold; CD4⁺: 2.3-fold); (2) Immunophenotype reprogramming via pro-inflammatory M1 macrophage skewing (M1/M2: 2.55 vs. 0.33); (3) Metastatic suppression (96% reduced distal tumor burden). This thermo-immunological nanoplatform establishes crosstalk between localized hyperthermia and antitumor immunity, advancing a translatable paradigm for TNBC management.