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PEGylated nanoparticles are known to improve LNP circulation half\u2010life and opsonization profiles. However, the drawbacks of PEG are hypersensitivity reactions due to pre\u2010existing PEG antibodies and poor biodegradability. These factors warrant a search for alternatives. Some large peptides have shown potent stealth properties in protein delivery. Here, we demonstrate that repeating units of serine\u2010threonine\u2010glutamic acid\u2010proline (STEP) peptide conjugated to dimyristoylglycerol (DMG\u2010STEP) and incorporated into lipid nanoparticles can perform as functional equivalents of DMG\u2010PEG. LNPs with DMG\u2010STEPs displayed similar physicochemical attributes and comparable Factor VII (FVII) silencing and human erythropoietin (hEPO) expression in both mouse and nonhuman primate animal models, with comparable biodistribution profile in mice. Additionally, DMG\u2010STEP LNPs encapsulating mRNA encoding for SARS\u2010CoV\u20102 Spike protein (Wuhan variant) demonstrated superior humoral immune response in a mouse study. In addition, the preliminary safety of STEP LNPs was demonstrated by quantifying liver enzymes, cytokine induction, complement activation, and anti\u2010STEP antibody production. Results demonstrated comparable or even reduced cytokine induction responses with STEP LNPs compared to control PEG LNPs. The data presented supports translational potential of STEP LNPs.<\/jats:p>","DOI":"10.1002\/adhm.202505392","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T21:47:30Z","timestamp":1773006450000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Peptide Substitutes of PEG: Biological Outcomes on Prospective Lipid Nanoparticle Shielding Materials"],"prefix":"10.1002","volume":"15","author":[{"given":"Rajesh","family":"Mukthavaram","sequence":"first","affiliation":[{"name":"Arcturus Therapeutics Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Tanis","sequence":"additional","affiliation":[{"name":"Arcturus Therapeutics Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Sagi","sequence":"additional","affiliation":[{"name":"Arcturus Therapeutics Inc.  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