Mucoadhesive tumor-penetrating nanomedicine for intravesical chemo-immunotherapy against bladder cancer.

Intravesical administrations of chemotherapeutics or immune-agonist Bacillus Calmette-Guérin (BCG) are first-line treatments for non-muscle-invasive bladder cancer (NMIBC). However, while urination prevents drug retention in the bladder, the bladder mucus, epithelial barrier, and dense tumor stroma form multiple physical barriers that restrict intratumoral drug penetration. Here, we developed thiol-functionalized bacterial membrane-coated nanoparticles loaded with a chemotherapeutic agent epirubicin (EPI) for highly effective intravesical chemo-immunotherapy against bladder tumors. The surface thiol groups enabled urine-resistant adhesion to the mucin-rich bladder mucosa through dynamic disulfide bonds, as demonstrated in both mouse and human bladders. Meanwhile, we unexpectedly found that bacterial membrane components up-regulated matrix metalloproteinases (MMPs), facilitating tight junction disruption and collagen degradation, thereby enhancing nanoparticle penetration into tumors. Intratumoral delivery of EPI by such nanomedicine would induce robust immunogenic cell death (ICD), which by synergizing with the immunoadjuvant properties of the bacterial membrane can elicit tumor-specific immune responses, resulting in potent antitumor efficacy in both NMIBC and muscle-invasive bladder cancer (MIBC) mouse models. Notably, combination with immune checkpoint blockade further amplified systemic antitumor immunity, leading to complete regression of orthotopic bladder tumors and marked inhibition of distant lesions. Our unique nanomedicine platform by addressing challenges in current intravesical therapies would be highly promising for potent intravesical chemo-immunotherapy of bladder malignancies.