The main challenge of chronic wounds is that they stop to heal and survive the skin functional integrity owing to severe weakening of the healing process and persistent inflammation and infection [1]. The delayed healing of chronic wounds is mainly related to the excessive or insistent inflammation due to M1-type macrophage polarization [2]. Current treatment of chronic wounds consists of traditional wound dressings, the use of off-loading devices, bioengineered skin substitutes, growth factors delivery, and autologous skin grafts [3]. Despite substantial efforts, the efficiency of chronic wound treatment remains limited, typically owing to the complexity of the healing process and very limited interventions in skin regeneration comprising biochemical, immune, and physiological repair processes [4]. Recently, immunomodulatory wound dressings have been introduced to control immune responses, improve angiogenesis, enhance re-epithelialization, and accelerate wound healing process. Here, we aim to synthesis and characterize nanocomposite hydrogels based on thiolated gelatin (Gel-SH) and methacrylate hyaluronic acid (MeHA) loaded with L-Arginine functionalized Poly(β-amino ester)/Alginate nanoparticles for chronic wound healing. Results showed poly(β-amino ester)/Alginate nanoparticles with average size of 200-600 nm were successfully incorporated within Gel-SH/MeHA hydrogel, in various concentrations (0-5 wt.%). In addition, the cumulative release of L-Arg and NO production led to enhanced keratinocyte proliferation and migration. In vitro experiments also confirmed that the hybrid hydrogel could modulate macrophage polarization to improve the local inflammatory microenvironment, and significantly accelerated the wound healing. Noticeably, the increase in the expression of the anti-inflammatory gene Arg-1 and a decrease in proinflammatory markers, including TNF-α, IL-1β, and IL-6 in RAW macrophages were reported when 2 wt.% Poly(β-amino ester)/Alginate nanoparticles were loaded in Gel-SH/MeHA hydrogel. Overall, this study demonstrates the potential of L-Arginine functionalized Poly(β-amino ester)/Alginate particles-laden hydrogels to accelerate chronic wound healing