Carrier-Free Nanoparticles Enhance Photothermal-Immune Therapy via Metabolic Reprogramming in Triple-Negative Breast Cancer.

A carrier-free co-assembled nanoplatform, designated as IR@PF-M NPs, was developed to enhance photothermal-immunotherapy against triple-negative breast cancer (TNBC) by reprogramming methionine metabolism. The nanoplatform was constructed through the self-assembly of the methionine adenosyltransferase 2A (MAT2A) inhibitor PF9366 with the near-infrared (NIR)-absorbing dye IR808, followed by surface modification with DSPE-PEG2000-Met. This formulation exhibited dual targeting capabilities, enabling tumor accumulation via the enhanced permeability and retention effect and selective uptake by tumor cells through overexpressed methionine transporters, which together enhanced intratumoral accumulation and photothermal efficiency. Upon NIR irradiation, IR808 generated potent photothermal effects with intratumoral temperature beyond 50°C that induced immunogenic cell death (ICD) and transformed the tumor microenvironment into an immune-activated ("hot") state. Simultaneously, PF9366 disrupted methionine metabolism, further amplifying ICD and suppressing TNBC progression and metastasis. By integrating photothermal therapy with metabolic intervention, IR@PF-M NPs demonstrated superior antitumor efficacy and immunomodulatory activity, offering a promising therapeutic strategy for TNBC management.