<p>Ventilator-associated pneumonia (VAP), predominantly caused by multidrug-resistant (MRD) gram-negative bacilli, remains a major challenge in intensive care units and leads to significant morbidity and mortality. The increasing ineffectiveness of conventional antibiotics emphasizes the urgent need for alternative therapies. This review analyses current evidence on nanotechnology-based delivery of antimicrobial peptides (AMPs) for treating MRD VAP. AMPs, essential components of the innate immune system with broad-spectrum activity, offer a promising therapeutic option. However, enzymatic degradation, poor bioavailability, short systemic half-life, and potential cytotoxicity limit their clinical application. Nanotechnology-based delivery systems, including liposomes, dendrimers, and polymeric nanoparticles, can overcome such barriers. These systems protect AMPs from enzymatic degradation, enhance their solubility, enable targeted delivery to the lungs, and reduce side effects on non-target tissues. However, advances in stimulus-responsive nanoplatforms, which release AMPs in response to infection-specific cues such as acidic pH or increased enzymatic activity, further enhance treatment precision and reduce systemic exposure. Preclinical studies demonstrate that nanoparticle-mediated AMP delivery effectively combats MRD VAP, underscoring its translational potential. This integrative approach, combining host-derived antimicrobials with advanced nanotechnology, represents a promising frontier in critical care. Its clinical adoption will require ongoing interdisciplinary research, standardized preclinical models, and regulatory harmonization.</p>