Dual-functional chitosan-hyaluronic acid dialdehyde nanoparticles for CD44-targeted Bcl-2 siRNA delivery and photothermal therapy in bladder cancer.

Bladder Cancer (BC) remains a major global health concern due to its high recurrence rate and limited availability of effective targeted therapies. Although gene therapy has emerged as a promising strategy, its clinical translation is hindered by the lack of safe and efficient delivery systems. This research aims to develop a dual-functional nanoparticle system for targeted gene delivery and enhanced therapeutic efficacy. Chitosan-Hyaluronic Acid Dialdehyde nanoparticles (CS-HAD NPs) were synthesized via controlled oxidation and covalent conjugation, enabling CD44 receptor-targeted delivery of Bcl-2 siRNA combined with near-infrared (NIR)-induced photothermal therapy. The optimized nanoparticles exhibited uniform size distribution, high siRNA encapsulation efficiency, and excellent colloidal stability. In vitro cellular assays demonstrated significant reductions in cell viability and Relative Growth Rate (RGR%), with the combined Bcl-2 siRNA@CS-HAD + NIR treatment showing maximum suppression over 24-72 h. Western blot and RT-qPCR analyses confirmed effective downregulation of Bcl-2 expression at both protein and mRNA levels. Hemocompatibility markers, including Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT), fibrinogen, Platelet Activation Marker (CD62P expression), and Complement Activation Marker (C3a level), remained within normal physiological ranges, indicating good blood compatibility. These findings demonstrate that the proposed dual-therapy system offers a synergistic anti-cancer effect through targeted gene silencing and photothermal action. The integration of CD44-targeted delivery with combined gene and photothermal therapy using a biocompatible nanoplatform presents a promising and safe approach for bladder cancer treatment, with significant potential for future biomedical applications. This research is limited to in vitro validation.