Mitochondrial-Disrupting Antimicrobial Peptide Nanoparticles as Precise Pyroptosis Inducers for Breast Cancer Immunotherapy.

Abstract

Breast cancer immunotherapy is limited by the intrinsically low immunogenicity of tumors, which restricts T cell activation and reduces therapeutic efficacy. Pyroptosis, a proinflammatory form of programmed cell death (PCD), provides a strategy to overcome this limitation by releasing damage-associated molecular patterns (DAMPs) and cytokines that coactivate innate and adaptive immunity. An antimicrobial peptide (AMP)-based pyroptosis inducer (API) is developed to selectively disrupt mitochondrial homeostasis and trigger potent cytotoxic T cell responses. API consists of amphiphilic copolymers p(PPE_m-co-AMP_n), in which AMPs are clustered on nanoparticle surfaces to facilitate cellular uptake. Upon exposure to intracellular reactive oxygen species (ROS), phenylboronic pinacol ester (PPE) linkages are cleaved, leading to nanoparticle disassembly into linear polymers. This transition restores the membrane-lytic activity of AMPs, enabling selective mitochondrial disruption and efficient pyroptosis. Using the model peptide (KLAKLAK)₂, API induces mitochondrial lysis and pyroptotic cell death, eliciting strong T cell activation. In a 4T1 breast cancer model, API treatment markedly suppresses tumor growth, metastasis, and recurrence without systemic toxicity. These results demonstrate API as a versatile nanoplatform for precise pyroptosis induction and highlight its promise for enhancing breast cancer immunotherapy.