The Crucial Role of Noncovalent Interactions in PLGA Nanoparticles: Impact on Carvacrol/ <i>p</i> -Cymene Release, Biological Activity, and Antibiofilm Properties

Understanding the molecular interactions between polymeric carriers and bioactive compounds is critical for designing advanced drug delivery systems. This study focuses on two nanoparticle systems composed of poly-(lactic-<i>co</i>-glycolic acid) (PLGA) encapsulating either carvacrol or <i>p</i>-cymene as model phytochemicals using a combined experimental and theoretical strategy. The nanoparticles were synthesized, characterized, and evaluated under physiological and bacteria-rich conditions, revealing distinct release behaviors: carvacrol displayed a rapid burst release aligned with potent antimicrobial activity, while <i>p</i>-cymene exhibited a delayed, bacteria-enhanced release. To elucidate the molecular origins of these behaviors, periodic Density Functional Theory calculations were performed, and Quantum Atoms in Molecules theory and Noncovalent Interaction Index analyses revealed stronger and more directional hydrogen bonds for carvacrol (-30.6 kcal/mol) versus dispersion-driven interactions for <i>p</i>-cymene (-23.4 kcal/mol), in agreement with experimental observations. Beyond controlled release, the nanoparticles demonstrated multifunctionality by simultaneously exerting antibacterial effects, modulating bacterial growth dynamics, sustaining antioxidant activity, even under biologically relevant stress conditions. Furthermore, a preliminary analysis of the interaction between bacterial biofilms and NPs was evaluated and correlated with in vitro and theoretical analyses. This work introduces a novel approach to studying phytochemical-polymer interactions, highlighting the power of theory-experiment integration for the rational design of advanced multifunctional nanocarriers based on natural therapeutics.