Endogenous Zinc Ion‐Triggered In‐Situ Gelation Enables Zn Capture to Reprogramme Benign Hyperplastic Prostate Microenvironment and Shrink Prostate

Abstract Benign prostatic hyperplasia (BPH) as the leading cause of urination disorder is still a refractory disease, and there have no satisfied drugs or treatment protocols yet. With identifying excessive Zn 2+ , inflammation, and oxidative stress as the etiology of aberrant hyperplasia, an injectable sodium alginate (SA) and glycyrrhizic acid (GA)‐interconnected hydrogels (SAGA) featuring Zn 2+ ‐triggered in situ gelation are developed to load lonidamine for reprogramming prostate microenvironment and treating BPH. Herein, SAGA hydrogels can crosslink with Zn 2+ in BPH via coordination chelation and switch free Zn 2+ to bound ones, consequently alleviating Zn 2+ ‐arisen inflammation and glycolysis. Beyond capturing Zn 2+ , GA with intrinsic immunoregulatory property can also alleviate local inflammation and scavenge reactive oxygen species (ROS). Intriguingly, Zn 2+ chelation‐bridged interconnection in SAGA enhances its mechanical property and regulates the degradation rate to enable continuous lonidamine release, favoring hyperplastic acini apoptosis and further inhibiting glycolysis. These multiple actions cooperatively reprogram BPH microenvironment to alleviate characteristic symptoms of BPH and shrink prostate. RNA sequencing reveals that chemotaxis, glycolysis, and tumor necrosis factor (TNF) inflammation‐related pathways associated with M1‐like phenotype polarization are discerned as the action rationales of such endogenous Zn 2+ ‐triggered in situ hydrogels, providing a candidate avenue to treat BPH.