ACS applied bio materialsOct 6, 2026

Fluorescent lipid nanoparticles designed to target two sites for improved small activating RNA delivery

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 7, 2026

Abstract

Dual-peptide-functionalized lipid nanoparticles (LNPs) demonstrate a 128% enhancement in protein expression compared to nonpeptide-functionalized LNPs.

A reactive copolymer platform based on poly(pentafluorophenyl acrylate) (PPFPA) facilitates the incorporation of surface functionalities into LNPs.
Optimal loading of 8 peptides per chain enhances cellular targeting.
Dual-peptide-functionalized LNPs show 7-fold and 5-fold increases in cellular uptake compared to single-peptide and nonpeptide-functionalized LNPs, respectively.
The copolymers maintain colloidal stability and low cytotoxicity while enabling fluorescence imaging and targeted delivery.

Simplified

Lipid nanoparticles (LNPs) are widely explored as delivery vehicles for self-amplifying RNA (saRNA); however, incorporation of surface functionalities, such as fluorescent dyes for imaging and ligands for targeted delivery, remains challenging. In this study, we introduce a reactive poly(pentafluorophenyl acrylate) (PPFPA)-based copolymer platform containing a terminal C12 alkyl chain for LNP incorporation and reactive sites for modular conjugation of near-infrared dye IR775, targeting peptides, and polyethylene glycol chains. The resulting copolymers are successfully incorporated into LNPs, enabling fluorescence imaging and targeted delivery while maintaining colloidal stability and low cytotoxicity. Systematic variation of peptide loading and composition identifies an optimal loading of 8 peptides per chain for cellular targeting. Additionally, dual-peptide-functionalized LNPs exhibit higher cellular uptake than single-peptide-functionalized LNPs, with 7-fold and 5-fold increases relative to nonpeptide-functionalized LNPs, respectively. This enhanced uptake translates into increased functional saRNA delivery, with the dual-peptide-functionalized LNPs showing a 128% enhancement in protein expression. These findings establish PPFPA-C12-based copolymers as a versatile platform for designing multifunctional LNP systems for RNA delivery.

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Fluorescent lipid nanoparticles designed to target two sites for improved small activating RNA delivery

Abstract

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