Diabetic foot ulcer (DFU), usually termed as diabetic wound, is a typical chronic wound, which may suffer from an incremental risk of recurrent infection and is prone to incur amputation or even death. These discomforts would turn into a critical threat to patients’ quality of health and life, and significantly enhance unaffordable healthcare costs [1], [2]. Accumulated evidences have asserted that diabetic wounds are implicated with cellular dysfunction, chronic inflammation and insufficient angiogenesis. Specially, the protracted inflammation is primarily brought on by excessive reactive oxygen species (ROS) and massive bacterial infection [3], [4], which would sustain the inflammatory state of wound and thus induce a prolonged wound healing [2], [5], [6], [7], [8], [9]. One of the most efficient ways to heal diabetic wound in clinical practice is hydrogel wound dressing, which is marked as its extracellular matrix (ECM) structure, strong water absorption, good biocompatibility, the capability to provide physical barrier against bacterial infection and absorb tissue exudates [10], [11]. Most importantly, as with three-dimensional network structure, hydrogel could be decorated by drugs or drug-like components to promote wound healing by continuous drug release [12], [13], [14]. Up to now, many pioneering achievements have been acquired, in which significant therapeutic effects were inspected in various skin wounds [15], [16]. However, it is realized that a majority of hydrogel wound dressings are composed of synthetic polymer composites, where the chemical synthesis may trigger potential toxic effect and unnecessary adverse immune reaction leading to a regressive biocompatibility [17], [18]. And the biodegradation of these polymer composites has aroused significant concerns. Furthermore, it is discovered that some of the leading hydrogel wound dressings focus their attentions on adjusting one pathogenic factor. This is seriously inadequate for clinical applications since the pathology of diabetic wound is extremely complex and the healing process is dynamically changing. It is these factors that make extant hydrogels difficult to meet the clinical needs for healing diabetic wound, hence exerting huge obstacle to impede the widespread clinical application of these hydrogel wound dressings. Obviously, endowing hydrogel with versatility via facile and sustainable strategy is crucial for curing refractory diabetic wound, but still highly challenging.

Recently, to construct carrier-free hydrogels using natural herbal small molecules have attracted extensive attentions, in which herbal small molecules with well-versed pharmaceutical effect were directly self-assembled via hydrogen bond, π-π stacking or electrostatic attraction [19], [20], [21], [22], [23], [24], [25]. In this system, herbal small molecules play the role of both carrier and cargo, and thus greatly improving the loading of insoluble drugs and sustaining continuous release for a long time. Otherwise, this type of hydrogel is also charactered as excellent biodegradability and metabolic capacity. More important, there is no need for chemical modifications in fabrication ensuring the availability and biocompatibility of hydrogel wound dressing. However, due to the extremely high requirements on molecular structure, the construction of herbal small molecule hydrogel remains in early stage of development leading to the rareness of this type of hydrogel [26]. Actually, our group had constructed a carrier-free hydrogel by direct assembly of mangiferin (MF), in which MF possessed antioxidation, antitumor activity, anti-inflammation, immunomodulation and antidiabetic activity, and performed hydrogel could expedite the healing of diabetic wound via inflammatory adjustment, collagen deposition, and angiogenesis [27]. Unfortunately, MF hydrogel (MFG) lacks robust bactericidal capacity to dispose bacterial infection in diabetic wound that has dramatically restricted the clinical transformation of this leading hydrogel. It is divinable that MFG embedded with bactericidal ingredients would better meet the requirements of clinical treatment of diabetic wounds.

The utilization of antibiotics, antimicrobial peptides and metal nanoparticles is popular for treating bacterial infection, among which metal nanoparticles have attracted considerable attentions due to the broad-spectrum antimicrobial activity [28], [29], [30], [31]. Silver nanoparticles (AgNPs) are deemed to be the most promising candidate to tackle bacterial infection as the remarkable antimicrobial activity, in which great progresses on both synthesis and biomedical applications have been achieved [32], [33], [34], [35], [36], [37]. Apart from this, the use of herbal small molecules with antibacterial activity appears to be an effective approach due to the low cost and easy access of herbal medicine [38], [39], [40]. Rhein (1,8-dihydroxy-3-carboxy anthraquinone, Rh) is a natural herbal small molecule usually found in Rhubarb and Cuspidatum, and has many pharmacological activities such as antibacterial property and anti-inflammation effect [26]. However, its low solubility in water and poor bioavailability limit the usage of Rh as a potential antibacterial agent. To fabricate a nano drug delivery system by the integration of Rh and AgNPs may conquer these deficiencies and further improve the bactericidal activity of them as the synergistic effect. And it is worth looking forward to the therapeutic effect for treating infected diabetic wound by embedding this nano drug into MFG.

Inspired by these, an herbal-based hydrogel was constructed by integrating MF, Rh and AgNPs, where MF was self-assembled into carrier-free hydrogel, and AgNPs were directly synthesized by Rh (Rh@Ag) accompanying with the implantation into MFG (Scheme 1A). The composite hydrogel (Rh@Ag-MFG) exhibits inherent bacteriostatic activity, ROS scavenging and hemostatic ability, and could mitigating inflammation response and expedite tissue regeneration by re-epithelization, collagen deposition and angiogenesis to accelerate infected diabetic wound healing. In this system, inherent bacteriostatic activity mainly derives from the synergistic effect of Rh and AgNPs, while antioxidation was attributed to the comprehensive effect of MF and Rh@Ag. Meanwhile, the green synthesis of AgNPs using Rh and utilization of carrier-free hydrogel immensely guarantee its safety that could facilite the widespread application of composite hydrogel in clinical practice. Furthermore, the graft of Rh on surface of AgNPs and hydrogelation of MF could significantly promote solubility of Rh and MF in water, thus increasing bioavailability to accelerate healing-related cell migration. Overall, the composite hydrogel could be regarded as wound dressing and possess huge potential for future clinical application to administrate refractory diabetic wound as the obvious effects on hemostasis, inflammation regulation, facilitating proliferation and remodeling phase (Scheme 1B).