Poly‐β‐Hydroxybutyrate Nanoparticles Improve Septic Immunoparalysis and Prognosis by Energy‐Refreshing via Controlled Release of β‐Hydroxybutyrate

Sepsis-associated immunoparalysis remains a key driver of poor clinical outcomes, yet no targeted pharmacotherapies have received clinical approval. Accumulating evidence identifies cellular metabolic dysfunction as a core pathogenic driver of this state, positioning metabolic modulation as a rational therapeutic approach. Biodegradable poly-β-hydroxybutyrate nanoparticles (PHB NPs) are fabricated via emulsion-solvent evaporation to address the short in vivo half-life and systemic adverse effects of free β-hydroxybutyrate (BHB), leveraging the intrinsic integrated carrier-prodrug nature of the PHB polymer.The optimized PHB NPs formulation exhibits uniform spherical morphology, extended circulation half-life, good biocompatibility, and broad tissue biodistribution. PHB NPs attenuate immunoparalysis both in vitro and in vivo, improve survival and restore immune responsiveness to LPS rechallenge in septic mice, and preserve cognitive function in surviving animals. Mechanistically, sustained BHB release from the nanoparticles restores cellular bioenergetics in immunoparalyzed cells through the tricarboxylic acid cycle-oxidative phosphorylation (TCA-OXPHOS) axis. These protective effects are recapitulated ex vivo in immunoparalyzed peripheral blood monocytes from a small cohort of septic patients.Collectively, these data indicate that PHB NPs ameliorate sepsis-induced immunoparalysis by restoring immune cell bioenergetics, and represent an energy-targeted nanotherapeutic candidate for further clinical development.