Antimicrobial Strategies for Chronic Cutaneous Ulcers: From Preclinical Nanotechnology to Clinical Practice.

Chronic cutaneous ulcers represent a growing global public health challenge, affecting an estimated 1-2% of the population in high-income countries and imposing a substantial socioeconomic burden through prolonged hospitalizations, repeated outpatient visits, increased risk of amputation, and significant impairment of patients' quality of life. Standard wound care centered on debridement, moisture-balancing dressings, and systemic antibiotics fails to resolve a large proportion of cases, particularly those complicated by polymicrobial biofilm infection and antimicrobial resistance, underscoring an urgent need for more effective therapeutic strategies. Despite the growing body of work on individual therapeutic modalities, no prior review has jointly evaluated clinically validated adjunct therapies and preclinical nanoplatform evidence for chronic cutaneous ulcers within a single, biofilm-ecology-centered framework, the gap this review addresses. This review critically evaluates current clinical and preclinical advances in the treatment of chronic cutaneous ulcers, with a focus on novel therapeutic modalities and emerging nanotechnology-based approaches. Clinically, the available evidence indicates that low-intensity ultrasound, electrical microcurrent therapy, photodynamic therapy, regenerative biomaterials, oxygen-based interventions, and advanced topical therapies may improve wound contraction, reduce microbial burden, relieve pain, and enhance tissue repair when used as adjuncts to standard care. At the preclinical level, metallic, polymeric, inorganic, and hybrid nanoplatforms can simultaneously target resistant bacteria and biofilms, stimulate angiogenesis, regulate inflammatory signaling, and support extracellular matrix remodeling. Recent advances in ulcer therapy are moving the field beyond passive wound coverage toward mechanism-driven treatments that actively modulate the chronic wound microenvironment. Despite this progress, current clinical evidence remains inconsistent and is often limited by small patient cohorts and non-standardized protocols. This highlights the pressing need for rigorous translational research to incorporate multifunctional bioactive platforms into well-supported, ulcer-specific therapeutic strategies.