A DNA-based nanorobot for targeting, hitchhiking, and regulating neutrophils to enhance sepsis therapy.

Summary

An Ac-PGP–modified tetrahedral DNA nanorobot binds neutrophil CXCR2, hitchhikes to inflamed tissues, and reprograms neutrophil maturation and functions to reduce oxidative stress and inflammatory recruitment, markedly decreasing sepsis-induced tissue damage in vivo. This demonstrates precise neutrophil-targeted delivery and regulation as a therapeutic concept.

Key Findings

• Ac-PGP–modified tetrahedral framework nucleic acid (APT) specifically binds neutrophil CXCR2 and hitchhikes to inflammatory sites, extending effective half-life.
• Internalized APT modulates neutrophil cell cycle and maturation, regulating oxidative stress, inflammation, migration, and recruitment in vitro and in vivo.
• In sepsis models, targeted neutrophil regulation by APT substantially reduced tissue damage.

Clinical Implications

While preclinical, the platform suggests a path to neutrophil-directed therapeutics that co-opt physiological trafficking. Translation will require immunogenicity, biodistribution, toxicity, and manufacturability assessments under GLP/GMP conditions.

Limitations

• Preclinical study without human data; immunogenicity and off-target effects on other CXCR2-expressing cells remain unknown.
• Long-term safety, clearance, and large-scale manufacturing feasibility not addressed.

Future Directions

Profile immunogenicity/toxicity and pharmacokinetics in large animals; evaluate efficacy in polymicrobial sepsis and comorbidity models; consider cargo loading or combinatorial immunomodulation.