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Yet, while RNA\u2010LNPs have reached clinical maturity, their DNA counterparts remain comparatively underexplored, despite holding great promise for gene replacement and genome\u2010editing therapies. In this review, we turn the spotlight on DNA\u2010loaded LNPs, examining how their structure, composition, and biological behavior differ from RNA\u2010LNPs, their natural point of reference, and from earlier lipid\u2010based systems such as cationic liposome\/DNA complexes (lipoplexes). DNA\u2010LNPs tend to form larger, more heterogeneous, and often multilamellar particles due to the intrinsic stiffness and high charge density of DNA. These distinctive features call for dedicated design strategies, including the use of cationic lipids, pre\u2010condensation agents, and optimized PEGylation schemes. Moreover, DNA profoundly influences the biomolecular corona that forms in biological fluids, which in turn shapes immune recognition, circulation, and tissue targeting. By highlighting these unique physical and biological challenges, this review underscores the need to move beyond simply adapting RNA\u2010based formulations. Instead, a cargo\u2010informed design approach will be key to unlocking the full therapeutic potential of DNA\u2010LNPs in next\u2010generation gene delivery.<\/jats:p>","DOI":"10.1002\/adhm.202505261","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T05:23:17Z","timestamp":1770096197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["From RNA to DNA: How Cargo Identity Reprograms Lipid Nanoparticle Architecture and Function"],"prefix":"10.1002","volume":"15","author":[{"given":"Erica","family":"Quagliarini","sequence":"first","affiliation":[{"name":"NanoDelivery Lab Department of Molecular Medicine Sapienza University of Rome  Rome Italy"},{"name":"Center For Nanotechnology Applied to Engineering (CNIS) Sapienza University of Rome  Rome 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