Targeted Nanoparticles for PROTAC-Mediated JAK1/JAK2 Degradation for Bladder Cancer Treatment

Although inhibition of the JAK-STAT signaling pathway has shown promise in cancer therapy, the therapeutic potential of PROTAC-mediated JAK1/JAK2 degradation in bladder cancer remains to be fully explored. To improve the delivery and therapeutic efficacy of PROTAC-mediated JAK1/JAK2 degradation in bladder cancer, this study developed PPcJ, a cRGD-functionalized PLGA-PEG nanoparticle encapsulating the PROTAC-based JAK1/JAK2 degrader JAPT8.

PPcJ nanoparticles were characterized using transmission electron microscopy, dynamic light scattering, and high-performance liquid chromatography. Flow cytometry and confocal microscopy were used to evaluate cytotoxicity, anti-tumor effect, and intracellular localization, while Western blotting assessed the expression of JAK/STAT pathway and apoptosis-related proteins. In vivo tumor-associated fluorescence, antitumor efficacy, survival, histopathology, and serum biochemical parameters were assessed in tumor-bearing mice.

PPcJ exhibited a spherical nanoscale morphology. PPcJ achieved near-plateau cellular uptake at low concentrations and partially evaded lysosomal degradation, which significantly induced apoptosis in bladder cancer cells and suppressed key components of the JAK/STAT signaling pathway. In vivo, cRGD modification enabled higher tumor-specific accumulation and prolonged retention. PPcJ inhibited tumor growth by 86.2% and prolonged mean survival from 22.4 ± 4.2 to 41.0 ± 2.2 days, without significant changes in body weight, major-organ histology, or serum AST, ALT, urea, and creatinine levels under the tested conditions.

These findings provide a preclinical proof-of-concept that the PPcJ nano-delivery system improves the delivery and antitumor performance of JAPT8. This strategy warrants further evaluation in systemic therapeutic approaches for bladder cancer.