mRNA encoding an Fc-free antibody fragment improves survival in mice with drug-resistant Pseudomonas lung infection
Background: A target distinct from those of antibiotics
Multidrug-resistant bacterial infections are difficult to treat with existing antibiotics, prompting the search for new approaches. A research team used messenger RNA (mRNA) technology to make cells produce an antibody fragment and observed improved survival in mice with Pseudomonas aeruginosa lung infection. The study did not test treatment efficacy in people.
The strategy targets the bacterium’s type III secretion system (T3SS), which injects toxins into host cells. The team encoded a single-chain variable fragment (scFv) that binds PcrV, a protein at the tip of this apparatus, in mRNA. Small antibody fragments generally disappear quickly from the bloodstream; the design aimed to address this limitation by sustaining their production in the body with mRNA.
Key findings: Delivery to the infection site and survival effects
The researchers compared an Fc-free scFv with an scFv fused to mouse Fc. Fc is an antibody region that contributes to its persistence in the body, among other functions. The study evaluated a strategy that targets PcrV to inhibit toxin delivery without Fc. A detailed structural model in which the antibody binds near the secretion pore and blocks toxin delivery was proposed using AlphaFold3 predictions; this should be distinguished from direct observation of physical blockage.
After intravenous administration of mRNA packaged in lipid nanoparticles (LNPs), antibody expression was observed mainly in the liver and spleen. The researchers interpreted the findings as indicating that secreted antibody reached the lungs through the bloodstream. Three hours after dosing, the concentration of Fc-free antibody in bronchoalveolar lavage fluid (BALF) was more than six times that of the Fc-fused form. In contrast, the Fc-fused form produced a stronger signal in whole-lung tissue. The small fragment’s advantage appeared in distribution toward the airway epithelium rather than in total lung accumulation.
Reduced lung inflammation and bacterial burden were observed mainly in a prevention experiment in immunocompetent mice given mRNA two hours before infection. Survival improvement was evaluated separately in a post-infection treatment experiment in immunocompromised mice. When Fc-free scFv mRNA was administered 30 minutes after infection with the multidrug-resistant clinical isolate KP2401, one-week survival was 45.5%; all mice in the control mRNA group died within 2–3 days.
The combination results with colistin are also notable. Combination treatment initiated at 30 minutes, 2 hours, 4 hours, or 8 hours after KP2401 infection yielded 100% one-week survival at every time point tested. Survival with monotherapy in those experiments was below 50%. These are results in mice; they do not mean the treatment is superior to antibiotics or can replace them in people.
Implications and outlook: Potential as an adjunct to antibiotics
The study presents an approach that combines sustained antibody production from mRNA with delivery of a small antibody fragment to the infection site. However, the Fc-fused form persisted longer in the body and showed an advantage under preventive conditions, so removal of Fc cannot be considered beneficial for every antibody treatment.
The researchers also assessed the therapeutic advantage of mRNA over direct administration of antibody protein as limited. Further development will require improvements to LNP and mRNA design, as well as validation of dose, timing, safety, and efficacy in people. Extension to other bacterial species remains a research possibility for Gram-negative bacteria that use T3SS in their pathogenicity. The evidence does not yet support extending these findings to personalized treatment across acute respiratory infections.
See the original Nature Communications paper for details.
In light of escalating antimicrobial resistance (AMR), alternative treatments to conventional antibiotics are imperative. This study demonstrates that mRNA-based therapeutics encoding single-chain variable fragments (scFv) antibodies—small, targeted antibody derivatives—provide robust defense against Pseudomonas aeruginosa, a prevalent multidrug-resistant pathogen. By focusing on the bacterial type III secretion system (T3SS), a critical toxin injection apparatus, the mRNA therapy effectively mitigates lung inflammation, reduces bacterial burden, and enhances survival rates in clinically relevant models, including immunodeficient mice infected with multidrug-resistant clinical isolates. The use of Fc-free scFv antibodies, which lack the Fc domain and thus exhibit superior tissue penetration, underscores enhanced therapeutic efficacy compared to larger antibodies with Fc regions. This mRNA-encoded approach represents a promising and adaptable platform for combating severe bacterial infections independently of traditional antibiotics.
Future development targeting drug-resistant Pseudomonas lung infections in immunocompromised patients could explore combining antibiotics with treatment directed at virulence factors. The rationale is the higher survival observed with colistin combination therapy than with monotherapy in the KP2401 mouse model. This should not be taken as a treatment recommendation for patients. The findings also suggest that development should assess distribution toward the airway epithelium, the actual infection site, alongside blood antibody levels and total lung accumulation. Appropriate dosing and treatment initiation timing in people, the safety of repeated dosing, and whether the combination effects can be reproduced in people remain to be established.