Triple-stimuli-responsive and FGL-1-inhibiting polydopamine nanoparticles for synergistic chemo-photothermal immunotherapy of breast cancer.

Combination therapies hold significant promise for breast cancer treatment; however, conventional delivery systems often lack precise control over intracellular drug release, limiting delivery efficiency and therapeutic synergy. To address this, we engineered triple stimuli-responsive nanoparticles (HAP/PDA NPs) by coating prodrug HA-PPT (HAP; HA = hyaluronic acid, PPT = podophyllotoxin) with ester and disulfide bonds onto polydopamine (PDA) cores for synergistically combining chemotherapy, photothermal therapy, and immunotherapy. HAP/PDA NPs exhibited tumor microenvironment-responsive drug release triggered by low pH, high glutathione levels, and localized heat, achieving a cumulative PPT release of 90.9% under triple-stimuli conditions. Furthermore, the NPs enhanced photpthermal therapy efficacy by downregulating heat shock protein 70 expression, mitigating thermoresistance. Notably, the mechanism involved suppression of the immune checkpoint fibrinogen-like protein 1 (FGL-1) by HAP/PDA NPs via the JAK2/STAT3 axis, with FGL-1 expression reduced to approximately 40% of the control level, thereby reversing immunosuppression to activate antitumor immunity and drive primary tumor regression. As a result, this multimodal approach enabled complete inhibition of tumor growth in some subjects and maintained high efficacy with a markedly lower PPT dose (one-third of the conventional dose). These findings offer a mechanistic paradigm for designing precision nanomedicines that co-target molecular and immune pathways for improved combination therapy in refractory breast cancer.