Chronic skin wounds are a major global health problem. They affect the health of millions of people and have major social and economic consequences. The wounds are diabetic foot ulcers, venous leg ulcers, and pressure sores [1,2]. They are characterized by ongoing inflammation, high protein breakdown activity, biofilm formation, and impaired blood supply, which inhibit tissue healing [3]. The conventional treatment is usually conventional wound dressings, hydrogels, and systemic antibiotics [4]. The treatments are ineffective because they are unable to release drugs at the right times and places, cannot penetrate deep into biofilm-infected wounds, and have side effects on the whole [5]. Advances in nanomedicine have led to the development of stimuli-responsive nanovesicles (SRNVs). These are new intelligent drug delivery systems that can detect the changing chemical and physical signals in chronic wounds [6]. These nanocarriers release drugs at the right times and places needed, stimulated by natural signals such as pH, reactive oxygen species (ROS), and enzyme activity, and external signals such as light, ultrasound, and magnetic fields. This allows a precisely controlled treatment regimen designed to the wound environment [7]. One possible challenge in treating chronic wounds is the presence of an unbalanced biochemical environment. This environment has a low acidic pH (4.0–6.5), high levels of ROS above 250 μM, and too much activity of certain enzymes called proteolytic enzymes. Chronic wounds are notorious for their hostile microenvironments. Elevated levels of proteolytic enzymes (Matrix-Metalloproteinase (MMP‐9)) surpassing 13 ng/mL and neutrophil elastase over 5 ng/mL [8] not only expedite tissue degradation but also undermine the stability of therapeutic agents by diminishing their bioavailability. In parallel, biofilm formation by pathogens like Pseudomonas aeruginosa which secretes exopolysaccharides (EPS) such as alginate, Pel, and Psl establishes dense diffusion barriers. This phenomenon is clearly illustrated by the reduced intrabiofilm concentrations of antibiotics: ciprofloxacin and gentamicin levels fall to 4.6 μg/mL and 5.8 μg/mL, respectively, significantly below therapeutic thresholds [9]. Consequently, standard antibiotics frequently falter against biofilm-embedded bacteria, underscoring the need for alternative delivery strategies.

One innovative solution lies in the development of SRNVs, engineered to exploit the wound's unique biochemical cues for localized drug release [10]. These nanocarriers can be designed using pH-sensitive polymers such as poly(β-amino esters) ROS-cleavable thioketal linkers, and enzyme-responsive MMP-labile peptides, ensuring that the release of therapeutics occurs precisely where needed [11]. Moreover, chronic wounds present additional mechanical challenges: necrotic tissue, surplus mucus, and an imbalanced immune response characterized by a skewed ratio of pro-inflammatory M1 to reparative M2 macrophages. Elevated cytokines, for instance, TNF-α (above 1.8 ng/mL) and IL-6 (up to 2.5 ng/mL), further extend the inflammatory phase and impede epithelialization [12]. Addressing these multifactorial issues, recent nanocarrier designs have begun to show promise. Mannose-functionalized lipid-polymer hybrid vesicles, for example, target M2 macrophages effectively, boosting the secretion of reparative transforming growth factor-β1 (notably, 3.1 ng/mL) and facilitating wound healing. In another approach, inflammation-activated nanovesicles loaded with dexamethasone encapsulated within ROS-degradable polymer shells have successfully reduced TNF-α levels to below 0.9 ng/mL within 48 h, demonstrating the capacity of these systems to rebalance the immune response. The creation of SRNVs is a deeply interdisciplinary endeavour. Advanced fabrication techniques, such as microfluidic assembly, yield vesicles with uniform size distributions, while hybrid structures that integrate lipids, polymers, and mesoporous silica scaffolds allow for the co-delivery of multiple antibiotics a strategy that has shown enhanced therapeutic synergy [13,14]. Beyond ensuring high drug-loading capacities and structural stability, these platforms also leverage targeted functionalization. For instance, the incorporation of integrin-binding RGD peptides promotes endothelial cell adhesion and angiogenesis at the wound site, and antimicrobial peptides (AMPs) like KSL-W disrupt biofilm integrity through electrostatic interactions. Complementary surface engineering, such as the application of zwitterionic phosphorylcholine-based coatings, minimizes immune detection by macrophages, thereby extending circulation times and enhancing localized drug retention. Together, these developments underscore the transformative potential of SRNVs in overcoming the complex biochemical and mechanical barriers that hinder the healing of chronic wounds. Translation of SRNV technology from the bench to bedside necessitates rigorous preclinical and clinical verification. Physiologically relevant in vitro and ex vivo models, such as 3D bioprinted chronic wound models with bacterial biofilms and gradients of hypoxia, provide nanovesicle penetration, bioactivity, and drug release kinetics [15,16]. Organ-on-chip microenvironments mimicking diabetic foot ulcer microenvironments have further progressed wound-on-a-chip technologies and enabled real-time monitoring of fluctuations in wound biomarkers [17]. In vivo efficacy experiments with murine wound models have quantitated primary therapeutic effects in terms of reduction of bacterial loads in log10 CFU/g, collagen deposition by Masson's trichrome staining, and macrophage polarization dynamics by flow cytometry [18].

This review presents an integrated perspective of SRNVs utilized in the therapy of chronic wounds, including their molecular pathobiology, advanced engineering techniques, preclinical evaluations, clinical uses, and their convergence with emerging technologies. By connecting basic research with translational nanomedicine, these developments have great potential to revolutionize therapy of chronic wounds by delivering target-specific, responsive, and sustainable therapies.