Using the intravesical delivery route to target the kidney.

Despite advances in drug delivery technologies, there is still an unmet demand for noninvasive kidney-targeted drug delivery systems that enhance therapeutic efficacy while minimizing systemic side effects. In the present study, we conducted a proof-of-concept study to evaluate the feasibility and effectiveness of intravesical delivery as a kidney-targeting strategy in mice. We demonstrated that intravesical infusion could retrogradely deliver molecules with a size up to 500 kDa to both the medulla and cortex of the kidney. In particular, empagliflozin, an antagonist of sodium-glucose cotransporter 2 (SGLT2), could effectively target the uppermost segment of the renal tubular system, that is, the proximal tubules, when administered via the intravesical route, thereby promoting glucose excretion. In an orthotopic renal carcinoma model, intravesical delivery of a chemotherapeutic agent achieved superior tumor suppression with markedly reduced adverse effects on extrarenal organs, compared with systemic administration at an equivalent dose. This improvement was attributed to a higher renal drug concentration and substantially lower systemic exposure achieved by intravesical delivery, demonstrating its kidney-targeting specificity. Thus, these findings indicated that the intravesical delivery route offers a promising strategy for kidney-targeted therapy and related translational research.NEW & NOTEWORTHY Intravesical infusion is valid for retrograde delivery of molecules up to 500 kDa to both the medulla and cortex of the kidney. This route is highly selective in targeting the urinary system with limited leakage to extrarenal organs, providing great potential as a noninvasive means for kidney-targeted research and therapy.