Spatiotemporally programmed core-shell multilayer hydrogel spheres dressing for scarless infected wound healing

Bacterially infected wounds often exhibit dysregulated inflammatory responses and ineffective pathogen clearance, leading to a dysregulated healing cascade and pathological scarring. Here, we present a spatiotemporally programmed core-shell hydrogel sphere system engineered via a molecular-weight-gradient hyaluronic acid (HA) architecture to modulate wound immune responses in a stage-matched manner. The outer layer composed of low-molecular-weight HA forms a relatively fast-eroding compartment, with acidic conditions further accelerating structural erosion, and is associated with enhanced early inflammatory activity. The intermediate layer incorporates reactive oxygen species (ROS)-responsive medium-molecular-weight HA functionalized with phenylboronic acid to enable stimulus-triggered release of caffeic acid, facilitating inflammatory resolution and transition toward a regenerative microenvironment. The inner core integrates high-molecular-weight HA with zwitterionic amine oxide (AO), forming a highly hydrated antifouling interface that suppresses nonspecific protein adsorption and supports extracellular matrix remodeling and is associated with reduced fibrotic remodeling. In addition, the hierarchical spheres exhibited rapid hemostatic performance through a multifactorial mechanism involving Ca²⁺-assisted coagulation. In vitro and in vivo results demonstrate antibacterial and anti-biofilm activity against methicillin-resistant Staphylococcus aureus (MRSA), together with enhanced angiogenesis and tissue regeneration. In a full-thickness MRSA-infected mouse model, the hydrogel significantly accelerated wound closure and enhanced tissue remodeling. Furthermore, in a rabbit ear scar model, the system reduced excessive scar formation and promoted more organized collagen remodeling, reflected by an improved collagen I/III ratio. Overall, this work establishes a molecular-weight-programmed, spatiotemporally responsive hydrogel platform for stage-specific regulation of infected wound healing and scar attenuation.