Engineered nanohybrids potentiate photothermal immunotherapy of breast tumor by optimizing deep tissue penetration and controlling secondary oxidative stress

Abstract

Photothermal immunotherapy holds promise for tumor suppression by synergizing localized hyperthermia with systemic immune activation. However, its translation faces critical barriers, including limited penetration of photothermal agents through the dense extracellular matrix (ECM) of solid tumors and heat-triggered ROS overproduction, which exacerbates immunosuppression by disrupting immune cell functionality. These challenges are particularly acute in triple-negative breast cancer (TNBC), characterized by its aggressive progression and immunosuppressive tumor microenvironment. To overcome these limitations, we engineered a multifunctional nanohybrid integrating zinc-ion-loaded layered double hydroxide (LDH) with small-sized poly-L-DOPA (PLD) nanoparticles, further complexed with losartan. This system leverages the acidic tumor microenvironment to sequentially release Zn²⁺ and losartan, which collaboratively remodel the ECM by upregulating matrix metalloproteinase-2 (MMP-2) activity and suppressing cancer-associated fibroblast (CAF)-driven collagen deposition. The optimized ECM permeability enhances tumor accumulation of PLD, a melanin-inspired polymer that simultaneously serves as a photothermal converter and ROS scavenger. Under near-infrared irradiation, PLD generates localized hyperthermia to induce immunogenic cell death, releasing damage-associated molecular patterns (DAMPs) that activate dendritic cells and prime cytotoxic T lymphocytes. Concurrently, PLD neutralizes excess ROS, alleviating oxidative stress and restoring the effector functions of CD4⁺/CD8⁺ T cells in residual tumor niches. By dual-targeting ECM remodeling and oxidative stress modulation, this nanoplatform achieves robust tumor eradication (91.5 % suppression rate) and immune microenvironment reprogramming, offering a transformative strategy to enhance photothermal immunotherapy for TNBC and other ECM-rich malignancies.