Macrophage-Targeting Lipid Nanoparticles (MacLNPs) Deliver siRNA Intranasally to Treat Viral Pneumonia

siRNA-LNP knock-down of TAK1 delivered intranasally and to macrophages specifically prevents inflammation-induced pathology in a mouse model
Problem:
Macrophages are an important component of the innate immune system, but can mediate excessive inflammation and cause severe pathology if left unchecked. This poses a challenge for the treatment of acute viral pneumonia. Methods like gene silencing may be effective to modulate inflammatory responses, but it is difficult to deliver therapeutics specifically to one cell type.
Solution:
The conventional cornerstone of treatment for viral pneumonia is supportive care. Through nasal delivery of MacLNPs, we can take an active role in treatment of this disease by limiting pathological inflammation. MacLNPs deliver their cargo to macrophages, which reduces the risk of off-target effects, and deliver gene therapies like siRNA, which are themselves techniques of precision medicine.
Technology:
The inventors screened LNP formulations for one that efficiently transfects siRNA (LNPsiMAX). They then conjugated the surface with an antibody raised against F4/80 (MacLNP), a surface marker of macrophages, to achieve targeted delivery. The inventors also show that MacLNPs can be used to deliver mRNA (GFP). In a preclinical disease mouse model, MacLNP delivery of TAK1-silencing siRNA reduced inflammation-induced lung pathology caused by acute influenza infection.
Advantages:

Nasal delivery of LNPs.
LNPs specifically deliver cargo to macrophages by F4/80 antibody conjugation.
Optimized LNP formulation for efficient siRNA delivery.
siRNA knock-down of TAK1 reduces influenza infection-induced pathology.

Stage of Development:

Target Identified
Preclinical Discovery

Figure 1. (A) Schematic describing the MacLNP development (from left to right): LNPs were screened for optimal delivery if siRNA (LNPsiMAX); conjugated to antibodies that bind F4/80, a cellular surface marker of macrophages, (MacLNP); a GFP mRNA expressed by MacLNP to validate specific delivery; TAK1 used in a mouse model of infection and to prevent inflammation. (B) Histological data between mice treated with PBS, MacLNPs carrying non-tageting siRNA, and MacLNPs carrying siRNA against TAK1, demonstrating that TAK1 knock-down prevented severe pathology.
Intellectual Property: