Inherently anti-metastatic peptide hydrogels for sonodynamic-amplified ferroptosis in cancer therapy

Cancer metastasis remains a significant challenge in oncology, prompting the exploration of innovative biomaterials to enhance treatment efficacy. While many hydrogels only serve as passive carriers, this study presents two novel self-assembling peptides, <b>CWEWTWY</b> and <b>NapFFSGP</b>, which form supramolecular hydrogels with intrinsic anti-metastatic properties. We demonstrate a correlation between the nanofibrous morphology of these peptides and their enhanced anti-metastatic activity, mediated by disruption of F-actin organization and impacting pathways related to cancer cell adhesion and actin filament dynamics. <i>In vivo</i> studies confirm a significant reduction in lung metastasis using a 4T1 pulmonary metastasis model. We also demonstrate their potential as a simple, synergistic platform integrating sonodynamic therapy (SDT) and ferroptosis. Ironporphyrin (FP), incorporated into <b>Gel@FP</b>, acts as both a sonosensitizer and ferroptosis inducer. Upon ultrasound irradiation, FP generates localized reactive oxygen species, further amplifying ferroptosis through enhanced lipid peroxidation. <b>Gel@FP</b> combined with ultrasound demonstrates potent antitumor efficacy <i>in vitro</i> and <i>in vivo</i>, promoting apoptosis, ferroptosis, and immunogenic cell death, leading to enhanced tumor regression and robust immune activation. Our findings highlight the potential of anti-metastatic hydrogels as a promising multifunctional platform to address the challenges of metastasis while enhancing antitumor immunity.