López Estévez, Ana MaríaSanjurjo, LucíaTurrero Braojos, ÁngelaArriaga, IkerAbrescia, Nicola G. A.Poveda, AnaJiménez-Barbero, JesúsVidal Figueroa, AnxoTorres López, DoloresAlonso Fernández, María José2025-02-212025-02-212024-07-18References López-Estévez, A. M., Sanjurjo, L., Turrero, Á, Arriaga, I., Abrescia, N. G. A., Poveda, A., Jiménez-Barbero, J., Vidal, A., Torres, D., & Alonso, M. J. (2024). Nanotechnology-assisted intracellular delivery of antibody as a precision therapy approach for KRAS-driven tumors. Journal of Controlled Release, 373, 277–292. 10.1016/j.jconrel.2024.07.0320168-3659https://hdl.handle.net/10347/39840The Kirsten Rat Sarcoma Virus (KRAS) oncoprotein, one of the most prevalent mutations in cancer, has been deemed undruggable for decades. The hypothesis of this work was that delivering anti-KRAS monoclonal antibody (mAb) at the intracellular level could effectively target the KRAS oncoprotein. To reach this goal, we designed and developed tLyP1-targeted palmitoyl hyaluronate (HAC16)-based nanoassemblies (HANAs) adapted for the association of bevacizumab as a model mAb. Selected candidates with adequate physicochemical properties (below 150 nm, neutral surface charge), and high drug loading capacity (>10%, w/w) were adapted to entrap the antiKRASG12V mAb. The resulting antiKRASG12V-loaded HANAs exhibited a bilayer composed of HAC16 polymer and phosphatidylcholine (PC) enclosing a hydrophilic core, as evidenced by cryogenic-transmission electron microscopy (cryo-TEM) and X-ray photoelectron spectroscopy (XPS). Selected prototypes were found to efficiently engage the target KRASG12V and, inhibit proliferation and colony formation in KRASG12V-mutated lung cancer cell lines. In vivo, a selected formulation exhibited a tumor growth reduction in a pancreatic tumor-bearing mouse model. In brief, this study offers evidence of the potential to use nanotechnology for developing anti-KRAS precision therapy and provides a rational framework for advancing mAb intracellular delivery against intracellular targets.eng© 2024 The Authors. Published by Elsevier B.V.Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/KRASCancerIntracellularmAb/monoclonal antibodyTargeted deliveryNanotechnologyjournal article10.1016/j.jconrel.2024.07.0321873-4995open access