Glycolysis inhibition via pH-responsive nanoparticles modulates macrophage reprogramming for sepsis immunotherapy

Sepsis persists as a life-threatening clinical syndrome associated with alarmingly high mortality rates, while existing therapeutic strategies demonstrate suboptimal efficacy, necessitating the development of novel interventions. In this study, we engineered pH-responsive nanoparticles (NPs) through an innovative one-pot synthesis utilizing FDA-approved poly-L-lysine (PLL) and cinnamaldehyde (CA), followed by hydrophilic-hydrophobic self-assembly with DSPE-PEG3400. The resulting NPs efficiently encapsulated the glucose transporter 1 (GLUT1) inhibitor BAY-876 (BAY-876@NPs) and exhibited microenvironment responsive drug release kinetics, wherein acidic inflammatory conditions induced protonation of BAY-876@NPs, facilitating controlled drug liberation. In both cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced sepsis mice, BAY-876@NPs demonstrated pH-dependent release of BAY-876, effectively attenuating GLUT1 mediated glucose uptake in macrophages. This mechanism concomitantly suppressed lactic acid accumulation and glycolytic flux, thereby reducing pro-inflammatory M1 phenotypes while augmenting anti-inflammatory M2 phenotypes. Consequently, BAY-876@NPs profoundly mitigated systemic inflammation, ameliorated multi-organ dysfunction, and significantly enhanced survival outcomes in septic mice. In summary, BAY-876@NPs exhibit superior biocompatibility and exert potent immunomodulatory effects by selectively inhibiting glycolysis, culminating in robust anti-inflammatory and organ-protective efficacy. These findings position BAY-876@NPs as a promising nanotherapeutic candidate for sepsis management. • Engineered pH-responsive nanoparticles via one-pot synthesis using FDA-approved poly-L-lysine/cinnamaldehyde and DSPE-PEG3400 for efficient BAY-876 encapsulation and acidic-triggered release. • Inhibited GLUT1-mediated glycolysis in macrophages via BAY-876@NPs, reducing lactate and reprogramming macrophages. • Improved survival in CLP/LPS-induced sepsis by reducing inflammation, enhancing M2 macrophages, and protecting organs through immunometabolic modulation.