Journal of controlled release : official journal of the Controlled Release SocietySep 27, 2025

Modified lipids with hydroxychloroquine reduce inflammation in mRNA treatments

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Hydroxychloroquine-functionalized ionizable lipids may reduce inflammatory responses while preserving mRNA delivery for repeated-dose therapeutic applications.

Evidence

Formulation and platform experiments characterized HCQ-functionalized lipid nanoparticles and tested them in mRNA expression, varicella-zoster virus vaccination, and PCSK9 CRISPR-Cas9 editing contexts.

Caveat

The abstract does not define the experimental models or report human clinical outcomes, so patient safety and efficacy remain unproven.

Simplified

Lipid nanoparticle (LNP)-based mRNA therapeutics, highlighted by the success of SARS-CoV-2 vaccines, face challenges due to inflammation caused by ionizable lipids. These ionizable lipids can activate the immune system, particularly when co-delivered with nucleic acids, leading to undesirable inflammatory responses. We introduce a novel class of anti-inflammatory ionizable lipids functionalized with hydroxychloroquine (HCQ), which suppresses both lipid-induced and nucleic acid-induced immune activation. These HCQ-functionalized LNPs (HL LNPs) exhibit reduced proinflammatory responses while maintaining efficient mRNA delivery. Structural and physicochemical analyses revealed that HCQ-functionalization results in a distinct particle structure with significantly improved stability. The efficacy of HL LNPs was demonstrated across various therapeutic contexts, including a prophylactic vaccination model against varicella-zoster virus (VZV) and CRISPR-Cas9 gene editing targeting PCSK9. Notably, HL LNPs showed robust mRNA expression after repeated administration, addressing concerns of inflammation and ensuring sustained therapeutic effects. These findings highlight the potential of HCQ-functionalized LNPs in expanding the safe use of mRNA therapeutics, particularly for applications requiring repeated dosing and in scenarios where inflammation-induced side effects must be minimized.