Endogenous Zinc-Ion-Triggered In Situ Gelation Enables Zn Capture to Reprogram 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 Zn²⁺ , inflammation, and oxidative stress as the etiology of aberrant hyperplasia, an injectable sodium alginate (SA) and glycyrrhizic acid (GA)-interconnected hydrogels (SAGA) featuring Zn²⁺ -triggered in situ gelation are developed to load lonidamine for reprogramming prostate microenvironment and treating BPH. Herein, SAGA hydrogels can crosslink with Zn²⁺ in BPH via coordination chelation and switch free Zn²⁺ to bound ones, consequently alleviating Zn²⁺ -arisen inflammation and glycolysis. Beyond capturing Zn²⁺ , GA with intrinsic immunoregulatory property can also alleviate local inflammation and scavenge reactive oxygen species (ROS). Intriguingly, Zn²⁺ 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 Zn²⁺ -triggered in situ hydrogels, providing a candidate avenue to treat BPH.

Keywords: Zn2+-crosslinked in situ gelation; benign prostatic hyperplasia; endogenous Zn2+ capture; glycolysis inhibition; inflammation microenvironment reprogramming.