Anthiya, ShubaashÖztürk, Süleyman CanYanik, HamdullahTavukcuoglu, EceŞahin, AdemDatta, DhrubajyotiCharisse, KlausMoreira Álvarez, DavidLoza García, María IsabelCalvo González, AlfonsoSulheim, EinarLoevenich, SimonKlinkenberg, GeirSchmid, RuthManoharan, MuthiahEsendağlı, GüneşAlonso Fernández, María José2023-05-302023-05-302023Journal of Controlled Release 357 (2023) 67-83http://hdl.handle.net/10347/30619K-RAS is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20–25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized lipid nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted lipid nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a pancreatic cancer murine model (subcutaneous xenograft CFPAC-1 tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a significant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reductioneng© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).http://creativecommons.org/licenses/by-nc-nd/4.0/RNA therapeuticssiRNATargeted deliveryLNPsKRASCombination therapyPancreatic cancerjournal article10.1016/j.jconrel.2023.03.0160168-3659open access