RT Journal Article T1 Surface-engineered gold nanorods for targeted delivery of PD-L1 siRNA and cancer chemo-phototherapy A1 Arellano, Lilia A1 Villar Álvarez, Eva A1 Cambón Freire, Adriana A1 Costa Santos, Alba A1 Pardo Montero, Alberto A1 Topete Camacho, Antonio A1 Barbosa Fernández, Silvia A1 Taboada Antelo, Pablo AB 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. PB Royal Society of Chemistry YR 2025 FD 2025-10-09 LK https://hdl.handle.net/10347/46922 UL https://hdl.handle.net/10347/46922 LA eng NO Arellano, L., Villar-Álvare, E., Cambón, A., Costa-Santos, A., Abelenda, Ó., Pardo, A., Topete, A., Barbosa, S., & Taboada, P. (2025). Surface-engineered gold nanorods for targeted delivery of PD-L1 siRNA and cancer chemo-phototherapy, Nanoscale, 17(44), 25537–25554. https://doi.org/10.1039/d5nr02667a NO The authors thank Agencia Estatal de Investigación (AEI) for funding through projects PID2022-142682OB-I00, PCI2022134981-2 and PID2023-152062OA-I00; and Xunta de Galicia for project ED431C 2022/28. European Regional Development Funds are also acknowledged. A. P. thanks Xunta de Galicia for grant ED481B2019/025. A. T. is thankful for the “Ramón y Cajal” fellowship RYC2023-045732-I funded by MICIU/AEI/ 10.13039/501100011033 and by ESF+. DS Minerva RD 9 may 2026