{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:14:57Z","timestamp":1791346497420,"version":"4.3.1"},"reference-count":136,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Optica Travel Lecturship Award"},{"name":"NIT-PhD scholarship","award":["ANRF\/SERBEEQ\/2023\/000669"],"award-info":[{"award-number":["ANRF\/SERBEEQ\/2023\/000669"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Lipid nanoparticles (LNPs) have become the cornerstone of nucleic acid delivery platforms, particularly in RNA-based vaccines and therapeutics. However, the conventional methods of LNP production, which are primarily reliant on microfluidic mixing of aqueous and organic solvent phases, pose limitations in terms of mRNA stability, residual organic contamination, scalability, cost, and environmental impact. These limitations prompted a renewed search for non-conventional strategies with the promise of improving mRNA-LNP encapsulation approaches. These emerging approaches aim to address key bottlenecks, including mRNA hydrolysis-driven degradation, high production losses, and complex downstream purification. Moreover, the ability to decouple LNP synthesis from mRNA encapsulation could enable streamlined, modular manufacturing workflows and customizable payload delivery, including single- or multiple-mRNA payloads, thereby expanding the therapeutic scope of LNPs. This review offers an early insight into the design principles and scalability potential of emerging non-conventional LNP encapsulation approaches, including solvent-free and microfluidics-free methodologies, and pre-built LNP workflows. We also examine trends in emerging LNP encapsulation tools, including high-shear mixing, sonication, membrane contraction, and other approaches. Finally, we extrapolate the suitability of the methods for scale-up approaches and their economic implications based on the process information.<\/jats:p>","DOI":"10.3390\/pharmaceutics18050527","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:43:51Z","timestamp":1777448631000},"page":"527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Emerging Non-Conventional Approaches in mRNA-LNP Formulation for Therapeutic Applications"],"prefix":"10.3390","volume":"18","author":[{"given":"Yitian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Bioengineering, Faculty of Engineering, McGill University, Montreal, QC H3A 0C3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Linaje-Ferrel","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Faculty of Engineering, McGill University, Montreal, QC H3A 0C3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7972-3221","authenticated-orcid":false,"given":"Juan Manuel","family":"Rocha Angel","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Faculty of Engineering, McGill University, Montreal, QC H3A 0C3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6188-6990","authenticated-orcid":false,"given":"Oindrila","family":"Banik","sequence":"additional","affiliation":[{"name":"OBMS Lab, Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6824-4675","authenticated-orcid":false,"given":"Earu","family":"Banoth","sequence":"additional","affiliation":[{"name":"OBMS Lab, Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-8815","authenticated-orcid":false,"given":"Amine A.","family":"Kamen","sequence":"additional","affiliation":[{"name":"Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H2X 1Y4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1516-6674","authenticated-orcid":false,"given":"Naresh","family":"Yandrapalli","sequence":"additional","affiliation":[{"name":"Department of Synthetic Biology, Gebaude B2.2, University of Saarland, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-9152","authenticated-orcid":false,"given":"Ayyappasamy Sudalaiyadum","family":"Perumal","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Faculty of Engineering, McGill University, Montreal, QC H3A 0C3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120586","DOI":"10.1016\/j.ijpharm.2021.120586","article-title":"mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability","volume":"601","author":"Schoenmaker","year":"2021","journal-title":"Int. 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