Human Leukocyte Elastase Triggered Nanoparticles for Targeted Antimicrobial Delivery and Oral Microbial Modulation

This study investigated targeted antimicrobial delivery through enzyme‐responsive polyelectrolyte complex (PIC) nanoparticles of peptides and antimicrobials. Nanoparticles released chlorhexidine upon enzymatic activation by human leukocyte elastase ( HLE ), mimicking conditions present at inflamed or infected sites, and utilized as a semi‐specific trigger for oral disease. Peptides P1‐P4 and P6‐P8 were tailored with HLE cleavable sequence alanine–alanine–proline–valine (AAPV) and flanked with cysteine and glutamic acid residues to enhance solubility, disulfide oxidation, and HLE sensitivity and specificity. Dynamic light scattering confirmed particle formation across various antimicrobial biguanide and peptide carboxylate ratios (N:COOH), with optimal size distribution and autocorrelation profiles observed for P7 (ECAAPVCE; N:COOH of 1:0.3). P7 ‐chlorhexidine‐based nanoparticles demonstrated structural stability in physiological conditions. Nanoparticle treatment of commensal Streptococcus sanguinis , and pathogenic Streptococcus mutans and Porphyromonas gingivalis delayed bacterial growth in a time‐, concentration‐, and HLE ‐dependent manner ( p < 0.05). Subinhibitory effects without HLE suggested residual chlorhexidine was below the minimum inhibitory concentration, while the presence of HLE enhanced antimicrobial effects, leading to complete inhibition of pathogenic species and transient growth inhibition of commensal species. These findings support development of HLE ‐responsive nanoparticle systems for targeted antimicrobial delivery, with potential for modulating microbial communities and providing site‐specific therapy in oral and other inflammatory infections.