Game-Changer for Drug-Resistant Pneumonia! Nature Biotech Unveils an mRNA Therapeutic Paradigm

Bacterial pneumonia remains a major global health threat, with multidrug-resistant (MDR) bacterial infections driving elevated treatment-failure rates and increased mortality. Conventional antibiotics exhibit limited efficacy, and excessive inflammatory responses further damage pulmonary tissue. Achieving both high-efficiency bacterial killing and simultaneous inflammation control has thus become an urgent unmet need.

 

Recently, the Yizhou Dong group at the Icahn School of Medicine at Mount Sinai published a study in Nature Biotechnology (IF = 41.7) entitled “Antimicrobial peptide delivery to lung as peptibody mRNA in anti-inflammatory lipids treats multidrug-resistant bacterial pneumonia.” Using a “peptibody mRNA + anti-inflammatory lipid” combination strategy, the team not only eradicated drug-resistant bacteria with high efficiency but also overcame multiple bottlenecks in pulmonary-infection therapy.

Research Concept: A Triple-Design “Smart Antibacterial System”

The essence of the work is the construction of an integrated therapeutic platform combining “precision delivery + on-demand activation + synergistic anti-inflammation.” In short, antimicrobial peptides are “manufactured on site” in the lung to kill pathogens accurately while simultaneously quelling inflammatory storms.

1. Molecular Engineering: An “On–Off Switch” for Antimicrobial Peptides

To overcome the poor stability and high cytotoxicity of free antimicrobial peptides, the team converted them into a “peptibody” format—equivalent to adding a dual insurance policy:

Fig. 1 Design and construction of mRNA encoding the peptibody

– Long-acting insurance: Fusion of an IgG1 Fc domain acts like a “battery pack,” prolonging serum half-life via FcRn recycling and promoting macrophage-mediated phagocytosis.

– Safety insurance: A cathelin domain serves as an infection-specific “switch”; neutrophil proteases at the infectious focus cleave this domain to release the active peptide, sparing healthy tissues and widening the therapeutic window.

After screening, LL37-derived PB9 emerged as the optimal candidate.

 

2. Delivery Revolution: Anti-Inflammatory Lipid Nanoparticles for Lung Targeting

Having solved “how to produce the peptide,” the team next tackled “how to deliver it to the lung.” A novel trisulfide lipid nanoparticle (TS41S LNP) was developed that functions as an “all-round courier”:

– Superior targeting: Lung delivery efficiency is 4.8-fold higher than that of the clinically used SM-102 LNP, with selective transfection of alveolar epithelial cells and macrophages.

Fig. 2 TS41S LNP delivery efficacy in pneumonic lung tissue

– Built-in anti-inflammatory buff: Trisulfide bonds scavenge reactive oxygen species (ROS) in the inflamed pulmonary microenvironment, reducing neutrophil infiltration and pro-inflammatory cytokine release—delivering drugs while “putting out the fire.”

Fig. 3 Anti-inflammatory capacity of TS41S LNP in pneumonic lung tissue

3. Efficacy Validation: Hard Data Outperforming Traditional Antibiotics

Performance in animal models propelled the platform into the spotlight:

Fig. 4 Therapeutic effect of TS41S LNP–PB9 mRNA in acute pneumonia models

– In an acute MDR pneumonia model, 14-day survival exceeded 75 % in the PB9 mRNA group, whereas the ciprofloxacin and control groups succumbed within 36 h.

– Pulmonary bacterial burden dropped by 4 log₁₀, with 60 % of mice achieving sterile blood cultures, preventing systemic dissemination.

– Human lung explants confirmed cross-species translatability; repeated dosing showed no hepatorenal toxicity, underscoring excellent safety.

 

This “peptibody mRNA + anti-inflammatory LNP” strategy truly achieves triple synergy—bactericidal killing, immune potentiation, and inflammation control—opening a new avenue for treating drug-resistant pneumonia.

 

Absin mRNA Solutions

Owing to unique advantages, mRNA technology is now deployed across diverse fields: rapid development of vaccines against SARS-CoV-2, influenza and other emerging pathogens; antigen delivery for cancer immunotherapy and CAR-T cell engineering; protein-replacement therapy, gene editing and tissue regeneration. Compared with conventional platforms, mRNA avoids nuclear entry and genomic integration, offers short development cycles amenable to rapid design and scalable manufacturing, and drives high-level target-protein expression for robust immune responses or functional protein replacement, providing a powerful and flexible precision-medicine toolkit. Absin supplies a one-stop mRNA portfolio, including custom mRNA synthesis, in-vitro transcription kits, tool mRNAs, and in-vitro / in-vivo transfection reagents.

 

Custom mRNA Services

Linear mRNA Workflow

Service specifications:

1. Standard capping: co-transcriptional chemical cap analog
2. Cap structure: AbsCap AG
3. Modified base: N1-Me-pUTP
4. UTR: Abs-CBT
5. Sequence design: 1 sequence (custom synthesis); ≥3 sequences (full service)
6. Minimum yield: 200 µg
7. QC: RNA integrity (RIN), denaturing gel image
8. Optional assays: cell-based expression validation, LNP encapsulation
9. Lead time: 2–4 weeks (custom synthesis, cell assays excluded); 4–8 weeks (full service)

 

Circular RNA Workflow

Service specifications:

1. Minimum yield: 200 µg per construct
2. Default IRES: Abs-IRES-G
3. Concentration: 1.0 µg µL^–1
4. QC: concentration, purity (A260/A280)
5. Minimum order: 1 construct (custom synthesis); ≥3 constructs (full service)
6. Lead time: 4–6 weeks (custom synthesis); 6–8 weeks (full service)

 

Representative Data

Linear RNA synthesis

Denaturing agarose gel of mRNA

 

Circular RNA synthesis

Denaturing agarose gel of circRNA

 

Fluorescence intensity comparison of linear vs. circular eGFP