Dual alarmin-receptor-specific targeting peptide systems for treatment of sepsis.
Summary
A dual-receptor blocking peptide (TMR) derived from HMGB1/PTX3 interaction motifs inhibited TLR4/MD2 and RAGE signaling, reducing HMGB1/PTX3- and LPS-driven cytokine release. Liposomal TMR improved pharmacokinetics, and antibiotic-loaded TMR-liposomes conferred significant therapeutic benefit in cecal ligation and puncture (CLP) sepsis. This establishes a late-mediator–targeted adjunctive strategy.
Key Findings
- TMR peptide disrupted HMGB1/PTX3 interactions with TLR4 and RAGE, attenuating cytokine production induced by HMGB1/PTX3 and LPS.
- Liposomal formulation (TMR-Lipo) improved peptide pharmacokinetics.
- Antibiotic-loaded TMR-Lipo produced significant therapeutic benefit in CLP-induced murine sepsis.
Clinical Implications
If translated safely to humans, TMR-based adjuncts could complement antibiotics by dampening late-phase inflammation (HMGB1/PTX3–TLR4/RAGE axis), potentially improving outcomes in severe sepsis.
Why It Matters
Introduces a mechanistically rational, dual-target strategy against late alarmins with in vivo efficacy, addressing prior failures of early cytokine blockade in sepsis.
Limitations
- Preclinical study without human safety or efficacy data
- Generalizability from CLP model and peptide-liposome PK/toxicity profiles remain to be established
Future Directions
Advance to GLP toxicology, pharmacokinetics, and dose-finding; test in larger animals; evaluate combinations with standard care; explore biomarker-guided selection (HMGB1/PTX3 levels).
Study Information
- Study Type
- Preclinical experimental study
- Research Domain
- Treatment
- Evidence Level
- V - Preclinical in vitro and animal model evidence without human clinical outcomes
- Study Design
- OTHER