Disassembly of Extracellular Matrix and Intercellular Adhesion Enables Noninvasive Bladder Cancer Disaggregation

Abstract

Bladder cancer is a type of prevalent malignant tumor of the urinary system, for which transurethral endoscopic resection serves as the first-line clinical treatment, followed by adjuvant intravesical chemotherapy or BCG immunotherapy. Current clinical regimens suffer largely from surgical trauma, procedural risks, long treatment cycles, severe systemic side effects, and high recurrence rates; conventional tumor cell-killing modalities relying on highly toxic chemotherapeutics and vaccines will inevitably damage normal tissues and induce less-tolerable adverse reactions in patients. By overturning this conventional therapeutic philosophy, we previously proposed a globally pioneering bladder cancer disaggregation therapy: calcium chelation disrupts intercellular cadherin-mediated adhesion, triggering exfoliation and detachment of tumor cells, which are subsequently excreted from the body via urine. Taking advantage of the unique anatomical and physiological characteristics of the bladder, this strategy achieves noninvasive tumor elimination through spontaneous urinary expulsion. To further enhance the disaggregation efficiency, the present work advances this concept by incorporating collagenase to realize the dual disruption of both cadherin and collagen proteins. To this end, we constructed a layered double hydroxide (LDH) nanoplatform coloaded with collagenase and EDTA. The nanosystem efficiently degrades key extracellular matrix components, thereby relieving steric hindrance and exposing cellular surfaces, which significantly promotes the subsequent disruption of intercellular junctions via enhanced EDTA accessibility for calcium deprivation from E-cadherin. This work establishes an efficient, noncell-killing modality for the physical clearance of bladder tumors, offering a promising alternative clinical strategy to suppress tumor recurrence and reduce systemic toxic side effects.