Magnesium Structure-Function Integration Platform for Spatiotemporal Multi-Modality Therapy: Combining Hormonotherapy and Immunotherapy in Prostate Cancer.

Metal-based immunotherapy represents a promising strategy for enhancing antitumor efficacy; however, its clinical application is limited by challenges such as inefficient drug delivery, low specificity, and suboptimal therapeutic outcomes. In this study, a therapeutic platform is constructed on a magnesium (Mg) surface utilizing self-healing thiolated hyaluronic acid (HA-SH) and cell membrane-derived vesicle (CMV) drug system, which improves structural stability, enables spatiotemporal drug release, and facilitates immune-hormone combination therapy for prostate cancer. CMV with phospholipid bilayers promotes HA-SH disulfide bond interactions through weak hydrophobic interactions, mitigating corrosion and ensuring structural integrity. Additionally, HA-SH exhibits glutathione (GSH)-responsive drug release within the tumor microenvironment. CMV facilitates pH-sensitive drug delivery and enables efficient cytoplasmic entry via membrane fusion mechanisms, ensuring precise spatiotemporal control. Through drug library screening, ginsenoside Rb1 is identified as a key therapeutic agent, competitively inhibiting androgen receptor signaling. Coupled with hydrogen release from Mg, it induces immunogenic cell death and promotes the formation of tertiary lymphoid structures (TLS) via inhibiting the PI3K-AKT pathway, achieving synergistic androgen deprivation therapy and immune activation. This implantable drug delivery system effectively tackles mechanical stability, local drug delivery, and systemic immune activation concerns, demonstrating substantial translational promise for various malignancies to improve treatment effectiveness and reduce structural failure risks.