Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape.

ABSTRACT: Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, but they induce severe inflammation. Here we show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo. Moreover, we show that a unique class of ionizable lipids can create smaller endosomal holes, reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Such lipids can produce high expression from cargo messenger RNA with minimal inflammation. Finally, we s

SUBMITTER: Omo-Lamai S 

PROVIDER: S-EPMC12352612 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature