Advances in phytochemical-derived nanotherapeutics for multimodal eradication of multidrug-resistant Staphylococcus...

The past decade, particularly the post-pandemic period, has intensified the challenge of managing bacterial infections. Multidrug-resistant Staphylococcus aureus (MDR-SA) has emerged as a dominant cause of hospital-acquired infections, creating a sustained public health emergency and underscoring the need for alternative antimicrobial strategies. Plant-derived secondary metabolites have gained attention as promising antibacterial agents; however, their therapeutic potential is constrained by poor solubility, limited target selectivity, low drug-loading capacity, rapid metabolism, and reduced systemic bioavailability. Nanoparticle carriers provide a corrective platform by improving physicochemical stability, enhancing solubility, enabling controlled release, and strengthening pharmacokinetic and pharmacodynamic behavior. Phytochemical-based nanoparticles (phyto-NPs) form a multitarget antibacterial architecture capable of weakening bacterial defense networks through efflux pump interference, disruption of metal-ion homeostasis, and alteration of membrane permeability. These systems also induce reactive oxygen species, leading to DNA damage, protein denaturation, mitochondrial impairment, and peptidoglycan disruption. In parallel, phyto-NPs inhibit biofilm formation and quorum-sensing pathways, reducing virulence and limiting dissemination. Their ability to penetrate the extracellular matrix enhances antibiotic access and restores susceptibility in resistant strains. Recent investigations demonstrate strong activity of phyto-NPs both as independent therapeutics and as synergistic partners to conventional antibiotics. Microenvironment-responsive release, intracellular targeting, and improved delivery efficiency further strengthen their translational relevance. Curcumin-loaded nanosystems disrupt MRSA membranes and impair biofilm formation, while quercetin-loaded liposomes penetrate S. aureus biofilms more effectively than free quercetin. These examples illustrate the capacity of nanoscale engineering to overcome the pharmacological constraints of phytochemicals. This review examines recent advances in phyto-NP strategies targeting MDR-SA, with emphasis on phytochemical selection, nanoscale design principles, and the multifunctional antibacterial mechanisms underpinning next-generation antimicrobial development.