Mucoadhesive and penetrating nanoparticles deliver Pt(IV) prodrug and STING agonist for enhanced intravesical bladder cancer therapy

Intravesical therapy is widely used in the management of bladder cancer. Nevertheless, continuous urinary flow accelerates the elimination of intravesically administered drugs, thereby reducing bladder residence time and therapeutic efficacy. Agents targeting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway have shown promising antitumor activity, yet their clinical translation is hindered by low local bioavailability and insufficient tumor selectivity. Here, a glutathione (GSH)-responsive nanoplatform, NP MP @Pt-MSA, was developed to integrate mucoadhesion with charge-mediated tissue penetration, thereby prolonging bladder retention and enhancing transurothelial delivery during intravesical administration. Upon cellular internalization, NP MP @Pt-MSA releases a Pt(IV) prodrug and the STING agonist MSA. DNA damage induced by the Pt(IV) prodrug promotes cytosolic dsDNA accumulation and activates the cGAS-STING pathway, while MSA further amplifies STING signaling, resulting in enhanced chemo-immunotherapeutic effects. In vivo, intravesical administration of NP MP @Pt-MSA significantly inhibited tumor growth, enhanced antitumor immune responses, and remodeled the immunosuppressive tumor microenvironment. Collectively, these findings establish a multifunctional intravesical delivery strategy that integrates mucoadhesive and tissue-penetrating nanoparticle design with dual chemo-immunomodulation, offering a promising approach to improve local therapy for bladder cancer. Graphical abstract