Intracellular Polymerization-Induced Self-Assembly of Peptide Nanosheets for Inflammatory Breast Cancer Therapy

Abstract Inflammatory breast cancer (IBC) is a highly aggressive breast cancer subtype characterized by diffuse, biologically invasive growth and poorly defined tissue boundaries, resulting in a high mortality rate even after multimodal treatment. Here, we report an intracellular polymerization-induced self-assembly (PISA) strategy that constructs mechanically active peptide nanosheets. Upon 365 nm UV irradiation, the photoinitiator Irgacure 2959 (I2959) initiates intracellular PISA of HisMAm in IBC cells. The corresponding nanosheets prepared in vitro exhibit a thickness of ∼30 nm and a wet-state apparent Young’s modulus of 8.02 ± 0.43 MPa. These nanosheets act through two coordinated materials-cell interactions: (i) increasing cellular viscosity and spatially associating with the actin cytoskeleton, suppressing cell migration and invasion; and (ii) accumulating in the endoplasmic reticulum and eliciting paraptosis-like cell death. In a subcutaneous IBC xenograft model, localized fiber-assisted light activation achieves 72.2% tumor growth inhibition without overt systemic toxicity. Overall, this work establishes intracellular PISA as a spatiotemporally controlled materials strategy for localized IBC treatment.