Nature: Prevention/treatment opens new doors, inhaled nanoparticles effectively deliver mRNA to the lungs

Nucleic acid drugs have high flexibility and can encode a variety of therapeutic proteins for therapeutic, prophylactic, or vaccine
use.
At present, the development and optimization of viral vectors such as lentiviruses and adeno-associated virus (AAV) and non-viral vectors such as lipid nanoparticles (LNPs) have greatly promoted the development of
nucleic acid drugs.
However, current nucleic acid delivery systems tend to be enriched in the liver
.
A large number of lung diseases, including COVID-19, influenza, cystic fibrosis, lung cancer, etc.
, urgently need a vector that can effectively deliver mRNA to the lungs and promote the prevention and treatment
of lung diseases through mRNA vaccines/therapies.

So far, the delivery of lung-targeted mRNA has basically been conducted in academic studies using polyethyleneimine (PEI) and lipid nanoparticles (LNP) in mice, and few
clinical trials have been conducted in humans.
One of the best-known clinical trials is aerosol preparation
of LNP-delivered mRNA for the treatment of cystic fibrosis.
Unfortunately, lung function did not improve
after treatment.

Recently, Philip Santangelo's team from Georgia Tech and Emory University published a research paper
titled "Species-Uncertain Polymer Formulations for Respirable Messenger RNA Delivery to the Lung" in the journal Nature Materials.
In this study, a polymer nanoparticle P76 was screened and identified, which can deliver various mRNAs to the lungs of different animals through aerosol inhalation, with high safety and tolerance
.

Functional screening of polymers for nebulized mRNA delivery

Studies in Syrian hamsters have shown that P76 can treat COVID-19 (SARS-CoV-2) infection
by aerosol inhalation by delivering mRNA encoding CRISPR-Cas13a.
Only 1/20 of the dose can achieve the effect
of high-dose neutralizing antibody therapy.
This study proposes a strategy to discover lung-targeted inhaled polymer formulations, opening a new door to the development of mRNA vaccines/therapeutics to prevent or treat lung diseases
.

In February 2021, Philip Santangelo's team published a paper in Nature Materials on the use of Poly-β-amino esters (PBAEs) aerosols to deliver CRISPR-Cas13a mRNA to the respiratory tract, which can effectively treat influenza virus and COVID-19 infection
in mice and hamsters 。 In this latest study, to improve the delivery of PBAE preparations to the lungs, the research team evaluated 166 PBAE and PBAE-containing preparations
in mice using a combined synthesis strategy and a low-dead volume nebulizer-based particle screening system.
In an initial screening, the team discovered P76, a poly β-aminothioester (PBATE).

PBATE can deliver mRNA to the lungs of mice, hamsters, ferrets, cows, and rhesus monkeys and is unaffected
by mRNA length and complexity.

More importantly, this study found that P76 is safe and well tolerated, and its expression of mRNA delivered by aerosol inhalation is higher than that of PBAE previously developed by this research team
.
The team conducted comparative experiments on Syrian hamsters and showed that spraying P76-delivered mRNA on CRISPR-Cas13a was effective in preventing weight loss in hamsters infected with COVID-19, and the dose used (50 μg) required only a quarter
of PBAE (200 μg).
In addition, the effect of this nebulized inhalation method is equivalent to direct intraperitoneal injection of high-dose anti-COVID-19 neutralizing antibody (1000 μg).

In total, P76 was screened and identified from 166 PBAEs and PBAEs-containing polymers as a highly efficient carrier for aerosol inhalation to deliver mRNA
.
It can also deliver mRNA to a variety of animals, including mice, large animal cattle, and non-human primates, rhesus macaques
.
This study also demonstrated in Syrian hamsters infected with COVID-19 that P76 can achieve similar efficacy to the gold standard (systemic neutralizing antibody therapy) at a low dose of 1/20 with minimal
toxicity.
P76 represents a significant advance in the preparation of polymeric nanoparticles that enables the future development of inhaled nucleic acid therapeutics
.

Rotolo L, et al.
Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung.
 Nature Materials, 2022: 1-11.