Harmonizing the Adhesion-Release Dilemma: Bio-based Injectable Hypertonic Hydrogel for Bladder Perfusion Therapy

Abstract

The high incidence of bladder diseases significantly impairs patients' quality of life, and there is an urgent need for improved local treatment strategies for superficial bladder cancer. However, conventional intravesical instillation suffers from short drug residence time (less than 2 hours) due to urine washout and lacks adequate wet adhesion to the bladder wall. Moreover, it remains challenging to achieve controlled drug release triggered by the pathological microenvironment (e.g., weak acidity and enzyme overexpression). While existing hydrogel materials often rely on strong covalent bonds (such as acrylates) for adhesion, such covalent networks tend to hinder drug diffusion, leading to burst release or an imbalance between adhesion and release performance. To address the limitations of current intravesical drug delivery systems, this study innovatively developed an injectable hydrogel system based on carboxymethyl chitosan (CMCS), oxidized hyaluronic acid (OHA), and tannic acid (TA). By constructing a dual dynamic cross-linking network via Schiff base bonds and hydrogen bonding, the hydrogel exhibits synergistic advantages in the hyperosmotic bladder environment: the polyphenol structure of TA provides strong wet adhesion to the bladder mucosa (adhesion strength >100 kPa), while the Schiff base and hydrogen bond networks enable pH/enzyme dual-responsive controlled drug release. Experimental results demonstrate that the system maintains stable drug release for over one week under simulated urine conditions, significantly enhancing antitumor efficacy. This study offers a new strategy to overcome the "strong adhesion–weak sustained release" dilemma and establishes a promising drug delivery platform with long-term retention and intelligent responsiveness for precise intravesical therapy of bladder cancer.