etc. Among them, hyaluronic acid (HA)derived hydrogel is one of the ideal candidates due to its inherent biological homology, feasible structure modification, as well as good degradability. [9,10] The high water retention capacity and high viscoelasticity of HA also allow it to be suitable for wound dressings.To construct desirable HA-based hydrogels, different strategies have been established. Relying on the intermolecular noncovalent interactions, the physical cross-linking HA hydrogels emerged. Rodell et al. developed a shearthinning and self-healing HA hydrogel due to the host-guest interaction between β-cyclodextrin (β-CD) and adamantine (AD) appended HA. [11] The hydrogel properties could be rationally tailored through the material concentration, degree of modification, and the ratio of β-CD to AD. Nevertheless, the physical hydrogels may exhibit undesirable mechanical properties and suffer from premature dissociation. Chemical crosslinking of pendant reactive groups by coordination chemistry or polymerization ignites an alternative route to fabricate HAbased hydrogels. In the meanwhile, transition metal ions or exogenous cross-linking agents usually involve, [12] which may impair the systemic biocompatibility due to their possible cytotoxicity. Recently, various compatible strategies have been proposed to develop biocompatible hydrogels, such as enzymemediated covalent linking, [13,14] disulfide cross-linking, [15,16] and Diels-Alder reaction. [17,18] Indeed, these chemical cross-linked hydrogels exhibit good mechanical property and are cytocompatible. However, their further applications are restricted by their limited functions. Thus, endowing HA hydrogels with multiple functions seems to be very promising, and fabricating HA-based functional hydrogels with good biocompatibility is still challengeable.In this study, a multifunctional hydrogel (PDA-HA) comprising of polydopamine (PDA) and thiolated hyaluronic acid (HA-SH) is developed (Scheme 1). PDA was introduced because of its good biocompatibility, strong tissue adhesion and effective free radical scavenging ability. Specially, it could act as the nanosized cross-linking agent that reacts with thiolated HA via Michael addition. The biocompatibility, gelling ability, tissue adhesion, free radical scavenging, and bacterial inhibition of the hybrid hydrogel were evaluated. The potential bacterial inhibition and good tissue adhesion endow the hydrogel with great potential for wound dressing.As shown in Figure 1A, thiolated hyaluronic acid (HA-SH) was obtained by two steps that referred to the amidation of Hyaluronic acid (HA)-based hydrogels have been receiving increasing attention for wound management. However, pure HA hydrogels usually exhibit weak mechanical strength and poor anti-infection. Herein, a hybrid HA-based hydrogel (PDA-HA) comprised of polydopamine (PDA) and thiolated hyaluronic acid (HA-SH) is developed based on the Michael addition reaction. The introduction of PDA into HA hydrogel can decrease the critical gel concentration, improve the c...

An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of D (KLAK) 2 peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged D (KLAK) 2 peptide with an α-helical conformation enabled rapid binding with microbial cells via electrostatic interaction and subsequent membrane insertion to deactivate the bacterial membrane. When triggered by Fe 2+ , moreover, LAHP could generate singlet oxygen ( 1 O 2 ) to elicit lipid bilayer leakage for enhanced bacteria inhibition. In vitro assays demonstrated that the combination strategy possessed excellent antimicrobial activity not only merely toward susceptible strains (Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli) but also toward methicillinresistant Staphylococcus aureus (MRSA). On the mouse skin abscess model induced by S. aureus, self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log 10 reduction) in the bioburden compared to that of the standard vancomycin (0.9 log 10 reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.

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