Black phosphorus nanomaterial nanocarriers for CD5L delivery: Targeted autophagy activation in sepsis lung injury

Sepsis-induced lung injury caused by multidrug-resistant <em>Pseudomonas aeruginosa</em> (MDR-PA) remains without effective therapeutic strategies. In this study, we developed a black phosphorus nanomaterial–based delivery system modified with the S2P peptide (BPNSs@S2P-CD5L) and elucidated its mechanism in ameliorating MDR-PA sepsis via the Cluster of Differentiation 36 (CD36)/phosphoinositide 3-kinase (PI3K) axis–mediated activation of microtubule-associated protein light chain 3 (LC3)-associated autophagy. Single-cell sequencing and transcriptomic analyses suggested that CD5 Antigen-Like (CD5L) may activate the PI3K axis by binding to CD36, thereby inducing autophagy. Functional assays confirmed that CD5L enhanced autophagic flux in macrophages through activation of the CD36/PI3K axis, which in turn alleviated inflammatory injury and promoted the phagocytosis and clearance of MDR-PA. A BPNSs@S2P-CD5L delivery system was successfully constructed, demonstrating good stability and biocompatibility with efficient targeting to lung tissue. Further investigations revealed that this system significantly attenuated oxidative stress and inflammatory responses in alveolar macrophages <em>in vitro</em>, while <em>in vivo</em> it markedly enhanced autophagic activity, bacterial clearance, and tissue repair, ultimately improving lung function and survival in MDR-PA septic mice. BPNSs@S2P/CD5L activates LC3-associated autophagy in macrophages via the CD36/PI3K axis, thereby enhancing their bacterial phagocytic capacity, reducing inflammatory responses and oxidative stress, and effectively alleviating lung injury induced by MDR-PA sepsis. These findings propose a novel nanomaterial–based immunomodulatory strategy for the treatment of drug-resistant bacterial sepsis, highlighting its potential for clinical translation.