000160874 001__ 160874
000160874 005__ 20251017144554.0
000160874 0247_ $$2doi$$a10.3390/pharmaceutics17040459
000160874 0248_ $$2sideral$$a144060
000160874 037__ $$aART-2025-144060
000160874 041__ $$aeng
000160874 100__ $$aHeredero, Juan
000160874 245__ $$aPredictive Lung- and Spleen-Targeted mRNA Delivery with Biodegradable Ionizable Lipids in Four-Component LNPs
000160874 260__ $$c2025
000160874 5060_ $$aAccess copy available to the general public$$fUnrestricted
000160874 5203_ $$aLipid nanoparticles (LNPs) are leading mRNA delivery vehicles, with ionizable lipids (ILs) as their key component. However, the relationship between the IL structure and LNP endogenous organ-targeting is not well understood. In this study, we developed a novel library of biodegradable ILs featuring beta-propionate linkers, which, when incorporated into a four-component LNP formulation, show excellent extrahepatic selectivity and high protein expression. Methods: We explored the impact of structural modifications in the hydrophobic chains and polar-head groups in the ILs while keeping the linkers unchanged. In vivo results were evaluated to examine how structural changes influence the biodistribution to spleen or lungs. LNP formulations were assessed for their protein expression levels and organ-specific targeting. Additionally, protein corona formation by the best-performing LNPs was examined to provide further mechanistic insights. Results: Organ targeting was significantly influenced by structural changes in the ILs, allowing for precise control of the biodistribution between the spleen and lungs. Branched hydrophobic chains demonstrated a higher propensity for spleen targeting, while modifications in the polar-head group could drastically shift biodistribution from the lung to the spleen. This led to the identification of LNPs’ zeta potential as a key determinant of their extrahepatic targeting properties. Notably, ionizable lipid A3T2C7, also known as CP-LC-1495, displayed strong lung selectivity (97%) and high protein expression in lung tissue (1.21 × 108 p/s). Similarly, several promising candidates for spleen-targeting LNPs displayed protein expression levels exceeding 1 × 107 p/s (selectivity >80%). Conclusions: This study elucidates the structure–function relationships of ILs in passive organ-specific mRNA delivery, highlighting how the fine-tuning of hydrophobic chains, polar-head groups, and surface charge (zeta potential) allows for the precise control of LNP endogenous biodistribution, a mechanism influenced by protein corona formation. These findings enable the rational design of targeted LNP systems, enhancing their therapeutic potential for specific organs, such as the spleen and lungs.
000160874 536__ $$9info:eu-repo/grantAgreement/ES/DGA/IDMF 2021-0009$$9info:eu-repo/grantAgreement/ES/MICIN/AEI/DIN2021-011799
000160874 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000160874 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000160874 700__ $$aPeña, Álvaro
000160874 700__ $$0(orcid)0000-0003-4155-749X$$aBroset, Esther
000160874 700__ $$aBlandín, Beatriz
000160874 700__ $$0(orcid)0000-0002-8486-8514$$aMiguel, Diego de
000160874 700__ $$0(orcid)0000-0002-9324-0446$$aAlejo, Teresa
000160874 700__ $$0(orcid)0000-0002-0087-7780$$aToro, Alfonso
000160874 700__ $$aMata, Elena
000160874 700__ $$aLópez-Gavín, Alexandre
000160874 700__ $$aGallego-Lleyda, Ana
000160874 700__ $$aCasabona, Diego
000160874 700__ $$aLampaya, Verónica
000160874 700__ $$aLarraga, Ana
000160874 700__ $$aPérez-Herrán, Esther
000160874 700__ $$aLuna, David
000160874 700__ $$aOrera, Irene
000160874 700__ $$aRomanos, Eduardo
000160874 700__ $$aGarcía, Alba
000160874 700__ $$0(orcid)0000-0002-8784-7735$$aMartínez-Oliván, Juan
000160874 700__ $$aGiménez-Warren, Javier
000160874 773__ $$g17, 4 (2025), 459 [18 pp.]$$pPharmaceutics$$tPharmaceutics$$x1999-4923
000160874 8564_ $$s2842413$$uhttps://zaguan.unizar.es/record/160874/files/texto_completo.pdf$$yVersión publicada
000160874 8564_ $$s3005185$$uhttps://zaguan.unizar.es/record/160874/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000160874 909CO $$ooai:zaguan.unizar.es:160874$$particulos$$pdriver
000160874 951__ $$a2025-10-17-14:12:32
000160874 980__ $$aARTICLE