Daniel Siegwart

Fun one for my chemist colleagues out there -innovative solutions for overcoming anti-PEG antibody challenges in LNPs! 🧬 LNP/mRNA are awesome tools, that's undeniable. However, a major hurdle has emerged: the widespread use of LNPs containing polyethylene glycol (PEG) has led to the development of anti-PEG antibodies in over a billion individuals, posing significant risks such as high reactogenicity and potentially life-threatening anaphylaxis. 🔬 Ok, so what is this PEG challenge and why, as a scientist, should care about it? Anti-PEG antibodies can compromise the effectiveness of LNP-based therapies, particularly in intravenously administered products, by triggering inflammation and complement-mediated inactivation. Current efforts to replace PEG with alternatives like polysarcosine (PS) and poly(2-ethyl-2-oxazoline) (PEOZ) have shown promise but are not without drawbacks, including the generation of anti-polymer antibodies and reduced efficacy with chronic use. 💡 A breakthrough with polyamides? This article highlights polyamides with short PEG grafts as a promising alternative. These polymers do not provoke anti-PEG antibody responses even after repeated administrations, thanks to their unique binding characteristics. Specifically, poly(L-glutamic acid) backbone esterified with oligoethylene-oxide grafts (PGE) of 2–5 units can replace PEG in LNPs, maintaining or exceeding the performance of traditional PEG-LNPs. ✨ And the key findings? 1) PGE3-LNPs, with 3-unit ethylene oxide grafts, demonstrated efficient mRNA transfection in vivo, particularly in the liver, and showed superior performance compared to PEG-LNPs during chronic administration. 2) These PGE-LNPs significantly reduce the generation of anti-PEG antibodies, addressing a critical barrier for long-term therapeutic use. 3) Variants with 2, 4, and 5-unit ethylene oxide grafts also achieved efficient cellular transfection, showcasing the broad potential of PGE-LNPs as next-generation stabilizers. 🚀 This study provides compelling evidence that polyamides with short PEG grafts can serve as effective, less immunogenic alternatives to traditional PEG in LNPs, paving the way for safer and more durable mRNA-based therapeutics. As we advance toward a new era of chronic administration of LNP-based therapies, the focus on rational polymer design will be key to unlocking their full potential. Learn more here: https://lnkd.in/eHwY6QtC #LipidNanoparticles #mRNA #DrugDelivery #Immunogenicity #PEGReplacement #Nanotechnology #Biotechnology

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Cell Metabolism

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