Structure-Activity-Driven Multicompartment Lipid Nanoparticles for Synergistic mRNA and siRNA Codelivery in Acute...

Area of Science:

• Biotechnology
• Nanomedicine
• Immunology

Background:

• Nonlamellar, multicompartment lipid nanoparticles (LNPs) are crucial for nucleic acid delivery and immunotherapy.
• Rational design of LNPs can optimize their internal structure for enhanced therapeutic efficacy.

Purpose of the Study:

• To develop imidazole-based LNPs (A3-DM/DL-LNPs) with a disordered sponge-like internal structure.
• To evaluate the codelivery of mRNA and STAT3-targeting siRNA (siSTAT3) using these novel LNPs.
• To assess the therapeutic potential of A3-DM/DL-LNPs in acute myeloid leukemia (AML) immunotherapy.

Main Methods:

• Small-angle scattering analysis to characterize LNP structure and internal arrangement.
• Raman spectroscopy to correlate lipid localization with RNA expression in immune organs.
• In vitro and in vivo studies to evaluate cellular uptake, transfection efficiency, and antileukemic activity.

Main Results:

• A3-DM/DL-LNPs exhibited a unique quasi-periodic arrangement with enhanced membrane heterogeneity, promoting endocytosis and RNA encapsulation.
• The "M-shaped" polar headgroup of A3-DM/DL-LNPs improved membrane interaction, cellular uptake, and transfection efficiency compared to linear headgroup LNPs.
• A3-DM/DL-LNPs restored dendritic cell antigen presentation, alleviated ER stress, reversed T cell exhaustion in AML, and enhanced NK and T cell-mediated antileukemic activity.

Conclusions:

• The rational design of imidazole-based LNPs with disordered internal structures enables efficient codelivery of mRNA and siRNA.
• LNP structure significantly influences immune activation and organ targeting, correlating with therapeutic outcomes.
• A3-DM/DL-LNPs demonstrate potent immunotherapeutic potential for AML by enhancing anti-leukemic immune responses.