Hydroxychloroquine-functionalized ionizable lipids mitigate inflammatory responses in mRNA therapeutics

Area of Science:

• Biotechnology
• Immunology
• Nanomedicine

Background:

• Lipid nanoparticle (LNP)-based mRNA therapeutics face challenges from ionizable lipids causing inflammation.
• Immune system activation by ionizable lipids and nucleic acids leads to undesirable inflammatory responses.

Purpose of the Study:

• To introduce a novel class of anti-inflammatory ionizable lipids functionalized with hydroxychloroquine (HCQ).
• To evaluate the potential of these HCQ-functionalized LNPs (HL LNPs) in reducing inflammation and improving mRNA therapeutics.

Main Methods:

• Functionalization of ionizable lipids with hydroxychloroquine (HCQ).
• Structural and physicochemical analyses of HCQ-functionalized LNPs (HL LNPs).
• In vitro and in vivo efficacy studies, including vaccination and gene editing models.

Main Results:

• HCQ-functionalization suppressed both lipid- and nucleic acid-induced immune activation.
• HL LNPs demonstrated reduced proinflammatory responses while maintaining efficient mRNA delivery.
• Improved particle stability and robust mRNA expression after repeated administration were observed.

Conclusions:

• HCQ-functionalized LNPs represent a promising strategy to mitigate inflammation associated with mRNA therapeutics.
• HL LNPs have the potential to expand the safe application of mRNA technology, especially for repeated dosing.
• These findings pave the way for safer and more effective mRNA-based treatments with minimized side effects.