Formulation Attributes and Preclinical Wound Healing Outcomes of Natural Product Based Nanoemulsions: A Systematic Review.

This systematic review integrates formulation composition and preparation methods with physicochemical characteristics and preclinical wound healing outcomes of directly applied natural product-based liquid nanoemulsions. PubMed and Scopus were searched through February 14, 2026, and the review was conducted in accordance with the PRISMA 2020 guidelines. The review protocol was registered in PROSPERO (CRD420261447376). Eligible studies directly evaluated liquid nanoemulsions as an intervention in in vitro or preclinical in vivo wound-healing models, without subsequent incorporation into a secondary dosage form, and reported physicochemical and/or wound-healing outcomes. Data were synthesized descriptively and narratively; meta-analysis was not performed because of substantial methodological and outcome heterogeneity. Eighteen studies were included, comprising 15 in vivo and three in vitro studies. Particle size, polydispersity index, and zeta potential were reported in 17, 16, and 14 studies, respectively. The median particle size was 120.10 nm (IQR, 46.68-212.00), median polydispersity index was 0.234 (IQR, 0.147-0.360), and signed zeta potential ranged from -40.20 to +44.40 mV. Physicochemical profiles varied substantially across active-material categories, compositions, concentrations, and preparation methods, and no universal physicochemical profile was consistently associated with biological performance. Most studies have reported improved wound contraction, closure, or wound size reduction relative to untreated or vehicle controls, whereas comparisons with standard treatments were inconsistent. Histopathological and mechanistic findings generally supported the macroscopic outcomes but remained heterogeneous. The risk-of-bias assessments for the 15 animal studies were dominated by unclear judgments, particularly for randomization, allocation concealment, random housing, and random outcome assessment, while blinding remained a major concern. Overall, the evidence suggests preclinical wound healing activity and formulation relevance; however, methodological heterogeneity and uncertainty in internal validity preclude conclusions regarding clinical efficacy, clinical superiority, or translational readiness.