Surface-engineered gold nanorods for targeted delivery of PD-L1 siRNA and cancer chemo-phototherapy.

Nowadays, cancer remains a global leading cause of death, with therapeutic advances often hindered by drug resistance and adverse side effects. The integration of nanotechnology with immunotherapy has emerged as a promising approach to enhance specificity and efficacy of oncological treatments. A key immunotherapeutic target is the so-called programmed death-ligand 1 (PD-L1), a protein that enables tumors to evade immune surveillance and increase their chemotherapy resistance. Interestingly, RNA interference using small interfering RNA (siRNA) targeting PD-L1, has shown potential in reactivating anti-cancer immune responses. However, efficient delivery of siRNA still faces challenges in terms of stability, cellular uptake, and/or targeted release. In this study, we developed a multifunctional theranostic nanoplatform based on gold nanorods (GNRs) surface-engineered through a layer-by-layer assembly with poly(styrene sulfonate), poly(L-lysine), and hyaluronic acid, to provide enhanced stability and active targeting towards CD44 receptors overexpressed in cancer cells. Within the polymeric multilayers PD-L1 siRNA, doxorubicin and indocyanine green were loaded for multimodal therapeutic activity. The anti-tumor effect, siRNA transfection efficiency and cell death mechanism of the nanoplatform was evaluated on HeLa cells expressing PD-L1 and CD44 and Balb/3T3 fibroblasts. The surface-engineered GNRs-based nanosystem efficiently transfected PD-L1 siRNA and allowed subsequent application of multimodal chemo-, photodynamic and photothermal therapy with enhanced cytotoxicity.