Cell-Derived Nanocarriers of Apoptotic Bodies with an Antimicrobial Peptide for Targeting Intracellular <i>S. aureus</i> Infections

Intracellular infections caused by <i>Staphylococcus aureus</i> are challenging due to their ability to evade host defenses, through the development of small colony variants (SCVs) that are resistant to conventional therapies. This study yielded and evaluated size-remodeled apoptotic bodies (ReApoBDs) as cell-derived nanocarriers for the targeted delivery of BotrAMP14, an antimicrobial peptide, to treat <i>S. aureus</i>-infected macrophages. ReApoBDs demonstrated high encapsulation efficiencies (∼70%), biocompatibility, sustained drug release over 12 h, colloidal stability, and improved intracellular delivery. The ReApoBDs-BotrAMP14 nanoformulation reduced intracellular bacterial loads while exhibiting lower cytotoxicity compared to the free peptide. Moreover, <i>in vivo</i> experiments demonstrated that ReApoBD-BotrAMP14 reduced dermonecrosis by 31.7% and SCV prevalence by 72.9%, more effectively than conventional treatments in a skin abscess model. Finally, the positive correlation between cell viability and bacterial survival highlights the challenge of designing treatments that effectively eliminate intracellular bacteria while preserving host cell integrity. As the first study to develop a ReApoBD-AMP formulation, these findings position ReApoBD-BotrAMP14 as a groundbreaking platform for treating persistent intracellular infections.