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Impaired diabetic wound healing is the most common complication in patients with diabetic hyperglycemia, which suffers from high morbidity, mortality, and recurrence rates and is the leading cause of nontraumatic limb amputations worldwide. (1,2) Increasing evidence suggests that defective angiogenesis significantly contributes to the debilitating conditions in impaired diabetic wound healing, which limits the delivery of crucial oxygen and nutrient to the wounded tissue thus impairing the wound healing process. (1,3,4) Furthermore, excessive oxidative stress also plays a critical role in the pathology of impaired diabetic wound healing. (5) Under this hostile wound microenvironment, the uncontrolled accumulation of reactive oxygen species (ROS) leads to significant destruction of endogenous stem cells, growth factors, and nucleic acids in the wounded tissue and thus greatly compromises their regenerative potential. (4,6−8) In addition, the externally administered proteins and nucleic acids are also highly vulnerable in the harsh diabetic wound microenvironment. (6,9) Moreover, it is noteworthy that these two pathological factors, defective angiogenesis and excessive oxidative stress, are not independent of each other since excessive ROS has been proposed to restrict angiogenic responses and result in endothelial dysfunction. (10,11) Current clinical therapies including debridement, antibiotics, blood-glucose control, and living skin-equivalent grafts mainly focus on preventing the expansion of the initial wound bed and infection. (12) Although symptom control maybe achieved by these standard therapies, therapeutics for effectively regeneration of the diabetic wound remains elusive. Unfortunately, ∼10% of diabetic wound patients will eventually undergo limb amputation. (12,13)

Among various efforts to address this urgent issue, reconstruction of functional vascularity is of vital importance. (3,14) Despite significant advances being made in improving angiogenesis in diabetic wounds by supplementing either angiogenic cells or growth factors, the achievements made so far have failed to translate into a meaningful clinical improvement because of a number of drawbacks. (15,16) A promising alternative to cells or growth factors for efficient angiogenesis is miRNA, (17) a class of highly conserved small noncoding regulatory RNAs, since accumulating evidence has demonstrated that miRNAs are involved in the development of defective angiogenesis. (18) Specifically, miR-26a has been recently identified as a key negative regulator of angiogenesis in diabetic wounds; inhibition of this miRNA may serve as a promising therapeutic modality. (18) Remarkably, targeting the disease-associated miRNA is a potentially more potent therapeutic strategy in comparison with single-target angiogenic growth factors since an individual miRNA with its pleiotropic effects can regulate multiple different genes and processes.

Although various nonviral or viral vectors have been explored for delivering these promising miRNAs in inhibition and replacement therapies, (19,20) an insurmountable obstacle is their rapid breakdown and inactivation in the hostile disease microenvironment, (9) which in the case of the diabetic wound, is the excessive oxidative stress. (6) Nevertheless, in addition to the diabetic wound, excessive ROS are also tightly linked with a myriad of serious diseases, where miRNAs could serve as promising therapeutic approaches. (21) Unfortunately, to the best of our knowledge, studies devoted to the design and construction of highly efficient miRNA carriers with a self-protecting capacity in the hostile oxidative disease microenvironment have been rarely reported so far. Meanwhile, engineering a friendly wound microenvironment is increasingly recognized as a novel paradigm for the successful healing of diabetic wound. (5,6) Accordingly, materials designed to simultaneously deliver proangiogenic miRNA cues (the “seed”) in a self-protecting manner and reshape the hostile oxidative wound microenvironment (the “soil”) are therefore highly desired yet challenging for functional angiogenesis and regenerative diabetic wound healing.

25K ) functionalized ceria nanocluster (PCN) antagomiR-26a (miR) nanocomplex (PCN-miR), which is designed to simultaneously reshape the hostile wound microenvironment (the “soil”) and provide proangiogenic cues (the “seed”) for diabetic wound repair and regeneration ( Recent advances in nanotechnology for biomedical applications have enabled elegant solutions for these problems. (22) As a representative nanozyme, ceria nanocrystals have recently drawn great attention in the treatment of oxidative-stress-associated diseases due to their facile synthesis, excellent biocompatibility, superior multiple antioxidant enzyme-mimetic activity, and rejuvenated catalytic performance. (23,24) These beneficial intrinsic properties of ceria nanozyme make it superior to other conventional antioxidant molecules or enzymes since they usually suffer from respective and collective drawbacks such as poor stability, high cost, scavenging only a single type of ROS, and nonrenewable ROS-scavenging capacity. (25) Furthermore, in comparison with the systemic administration route, we hypothesize that topical miRNA delivery by an miRNA-containing hydrogel depot may be favorable for their therapeutic effects in a site-specific manner, without raising concerns about systemic toxicity and off-target side effects. (26−28) On the basis of these considerations, herein we introduce a unique “seed-and-soil” strategy for enhanced diabetic wound healing using a nanozyme-reinforced self-protecting hydrogel (PCN-miR/Col) composed of 25 kDa polyethylenimine (PEI) functionalized ceria nanocluster (PCN) antagomiR-26a (miR) nanocomplex (PCN-miR), which is designed to simultaneously reshape the hostile wound microenvironment (the “soil”) and provide proangiogenic cues (the “seed”) for diabetic wound repair and regeneration ( Figure 1 A,B). The natural extracellular matrix protein collagen was employed for the construction of the hydrogel, which serves as a favorable platform for the integration of the PCN-miR. AntagomiR-26a was utilized to inhibit the antiangiogenic miR-26a, a well-established hyperglycemia-induced target that is responsible for impaired angiogenesis in diabetic wounds. (18) Benefited from the highly efficient ROS-scavenging activities, PCN-miR/Col not only enable reformation of the hostile oxidative wound microenvironment, but also protect the encapsulated miRNAs against ROS-induced damage. Because of the extraordinary synergy, augmented functional blood vessel growth and oxygen saturation were achieved, resulting in an accelerated wound closure and a superior quality of the newly healed wound featured by ordered alignment of collagen fiber and skin appendage morphogenesis. The proposed “seed-and-soil” strategy is applicable to the repair and regeneration of a broad range of damaged tissues, which suffer from highly oxidative diseased microenvironments and dysregulated bio-macromolecules.