State-dependent urothelial barrier engineering for intravesical biomaterials: retention, restoration, and navigation

Intravesical biomaterials operate at an interface whose therapeutic role changes with disease state. In inflammatory bladder disease, urothelial abnormalities can become targets for repair; in non-muscle-invasive bladder cancer (NMIBC), the same interface can restrict access to superficial or deeper therapeutic targets. Existing reviews commonly organize these materials by carrier class or therapeutic modality, but such classifications do not explain why the same property—strong adhesion, increased permeability or prolonged persistence—can be beneficial in one setting and counterproductive in another. Here, we organize the field around three variables: urothelial barrier state, target location or depth, and treatment phase. These variables define three recurring material functions: RETAIN sufficient local exposure, RESTORE a measurable disease-relevant urothelial abnormality, and NAVIGATE to a therapeutic compartment beyond the luminal surface. Evidence from IC/BPS, chemical and radiation cystitis, human bladder pharmacokinetics and emerging NMIBC delivery systems shows that these functions frequently overlap but require different readouts. Structural recovery is not equivalent to functional barrier restoration, and greater tumor accumulation or penetration does not by itself establish cellular uptake or target engagement. A state-dependent view therefore shifts intravesical biomaterial design away from maximizing isolated material properties and toward matching the material–urothelial interaction to a defined therapeutic task, while accounting for normal-urothelial safety and post-treatment recovery.