Fibroblast growth factor receptor 3 (FGFR3) is a key oncogenic driver in bladder cancer (BCa). Although erdafitinib, the pioneering FGFR3 inhibitor, is approved for clinic use, its oral administration frequently causes inadequate therapeutic effect and side effects. Here, we report a pH-responsive and erdafitinib-loaded liposomal nanosystem with surface modification of anti-FGFR3 antibodies (Phl-erda@Ab), which demonstrates improved antitumor effects in intravesical instillation therapy. In RT112 cells, we evaluated targeted uptake and antiproliferative activity. In vivo, we assessed intravesical retention, antitumor efficacy, and histopathological markers (TUNEL, Ki67) in a BCa xenograft BALB/C nude mouse model, alongside systemic safety profiling. The Phl-erda@Ab exhibited sharp pH sensitivity, releasing 49% of the drug payload within 1 h at pH 5.3 while maintaining minimal release at pH 7.4 and 6.5. Liposome retention after intravesical instillation was doubled compared with non-targeted Phl-erda in mice. The Phl-erda@Ab intravesical therapy demonstrated effective antitumor activity, including maximal necrosis, the highest TUNEL-positive apoptotic index, and the lowest Ki67 proliferation index, compared to other groups. No significant pathological damage to major organs was observed. In summary, Phl-erda@Ab enables FGFR3-targeted, pH-triggered intravesical delivery with enhanced intravesical retention, improved antitumor activity, and favorable local safety, providing preclinical evidence to support clinical translation in FGFR3-overexpressing BCa.

Drug-mediated intravesical therapy is a widely used treatment approach for bladder cancer (BCa), which is limited by poor tumor accumulation and the toxicity of drugs. Herein, a facile approach utilizing magnetic hyperthermia therapy (MHT) for BCa treatment is reported through intravesical instillation of tumor-targeting iron oxide nanoparticles (IONPs), which are coated with anti-FGFR3 antibodies for specific binding to FGFR3 overexpressed on BCa cells. The antibody coating significantly enhanced targeting ability and increased cancer cell uptake. Under an alternating magnetic field (AMF), the IONPs magnetothermally activated TRPV1 on the endoplasmic reticulum (ER) of BCa and induced Ca²⁺ overload in RT4 BCa cells. The magnetothermal treatment significantly upregulated the pro-apoptotic gene expression of Bax, Pro-caspase-3, and Cytc in RT4 cells, and downregulated the anti-apoptotic effector gene Bcl-2, ultimately causing augmented apoptosis in cancer cells. The application of intravesical FGFR3-targeting MHT successfully resulted in greater suppression of tumor growth and improved survival rate of mice, compared to the control, IONP, and AMF-treated groups. These results hold significant potential as a transformative modality toward BCa therapeutic application.