Ultrasound-responsive chitosan-based hydrogels for intravesical chemotherapy: mechanisms, design strategies, and translational perspectives.

Intravesical therapy remains the standard treatment for non-muscle-invasive bladder cancer (NMIBC), yet its clinical efficacy is limited by significant biological, pharmacological, and procedural barriers. Conventional intravesical drug instillation requires repeated hospital visits and urethral catheterization, which may reduce patient compliance owing to discomfort, urethral trauma, and an increased risk of urinary tract infections. Therapeutic performance is further compromised by rapid drug dilution, frequent bladder emptying, and the dynamic urinary environment, resulting in a short intravesical residence time. Biological barriers, including the exceptionally tight urothelial permeability barrier (transepithelial electrical resistance >10 000 Ω cm2), comparable to the blood-brain barrier, and the hypoxic tumour microenvironment, further restrict drug penetration, leaving less than 5% of the administered dose available at the tumour site. Escalating drug concentrations to compensate for poor penetration frequently results in chemical cystitis and other local adverse effects. Among emerging biomaterials, chitosan has attracted considerable attention owing to its excellent mucoadhesive properties, transient modulation of urothelial tight junctions, favourable biocompatibility, and biodegradability, making it an attractive platform for prolonged intravesical drug retention. Genipin has emerged as the most widely investigated natural crosslinker because of its low cytotoxicity, tunable crosslinking properties, and ability to improve the mechanical stability and sustained-release behaviour of chitosan hydrogels. Integration of ultrasound as a non-invasive external stimulus, particularly through microbubble-mediated cavitation and sonoporation, further enables spatiotemporally controlled drug release and enhanced urothelial permeability. In this review, we critically discuss the biological barriers to intravesical drug delivery and highlight recent advances in ultrasound-responsive chitosan-genipin hydrogels as multifunctional platforms for NMIBC therapy. We evaluate crosslinker safety, strategies for overcoming tumour hypoxia, and preclinical evidence demonstrating prolonged bladder retention (>72 h), 2-3-fold enhanced tissue penetration, and tumour inhibition of 60-80%. Finally, we discuss key translational challenges, including scalable manufacturing, regulatory considerations, patient heterogeneity, and long-term safety, while outlining future opportunities in theranostic hydrogels, microrobots, closed-loop drug delivery, and multi-stimuli-responsive biomaterials. Collectively, ultrasound-responsive chitosan-genipin hydrogels represent a promising intravesical platform capable of enhancing therapeutic efficacy while minimizing treatment-related toxicity in NMIBC.