Unimolecular Cascaded Multienzyme Conjugates Modulate the Microenvironment of Diabetic Wound to Promote Healing.

An abnormal microenvironment underlies poor healing in chronic diabetic chronic wounds. However, effectively modulating the microenvironment of the diabetic wound remains a great challenge due to sustained oxidative stress and chronic inflammation. Here, we present a unimolecular enzyme-polymer conjugate that demonstrates excellent multienzymatic cascade activities. The cascaded enzyme conjugates (CECs) were synthesized by grafting poly(N-acryloyl-lysine) (pLAAm) from the glycan moieties of glucose oxidase (GOx) via glycan-initiated polymerization. The resulting CECs exhibited multiple enzymatic properties of GOx, superoxide dismutase mimic, and catalase mimic activities simultaneously. The CECs facilitated the depletion of high blood glucose, ROS scavenging, bacteria-killing, anti-inflammatory effects, and sustained oxygen generation, which restored the microenvironment in diabetic wounds. In vivo results from a diabetic mouse model confirmed the capacity and efficiency of the cascade reaction for diabetic wound healing. Our findings demonstrate that the three-in-one enzyme-polymer conjugates alone can modulate the diabetic microenvironment for wound healing.

Glycan-selective in-situ growth of thermoresponsive polymers for thermoprecipitation and enrichment of N-glycoprotein/glycopeptides.

In view of the biological significance and micro-heterogeneity of protein glycosylation for human health, specific enrichment of N-glycosylated proteins/peptides from complex biological samples is a prerequisite for the discovery of disease biomarkers and clinical diagnosis. In this work, we propose a "grafting-from" N-glycoprotein enriching method based on the in-situ growth of thermoresponsive polymer brushes from the N-glycosylated site of proteins. The initiator was first attached to the pre-oxidized glycan moieties by hydrazide chemistry, from which the thermoresponsive polymers can be grown to form giant protein-polymer conjugates (PPC). The thermosensitive PPC can be precipitated and separated by raising the temperature to above its lower critical solubility temperature (LCST). Mass spectrometry verified 210 N-glycopeptides corresponding to 136 N-glycoproteins in the rabbit serum. These results demonstrate the capability of the tandem thermoprecipitation strategy to enrich and separate N-glycoprotein/glycopeptide. Due to its simplicity and efficiency specifically, this method holds the potential for identifying biomarkers from biological samples in N-glycoproteome analysis.

Hyaluronic acid-targeted and pH-responsive drug delivery system based on metal-organic frameworks for efficient antitumor therapy.

Drug delivery systems (DDSs) have emerged to help delivering the required cargo into the region of the tumor, achieving the objectives of extenuating the potential damage to the body and improving the therapeutic effectiveness. Here, we developed a one-pot process for encapsulating the unstable and hydrophobic d-α-Tocopherol succinate (α-TOS) in zeolitic imidazolate framework-8 (ZIF-8) compounds (defined as α-TOS@ZIF-8) and subsequently coated with a hyaluronic acid (HA) shell to form the HA/α-TOS@ZIF-8 nanoplatform. Of particular note was when the concentration of α-TOS is l mg/mL, the loading rate was high up to 43.03 wt%. The study verified that HA shell, which could act as a smart "switch" and tumor-targeted "guider", had the capacity for extending blood circulation, enhancing the tumor-specific accumulation of DDS via CD44-mediated pathway. HA shell could be disintegrated by hyaluronidase (HAase) in the tumor microenvironment (TME) and the wrapped α-TOS@ZIF-8 exposed, thus leading to the decomposition of ZIF-8 in tumor acidic microenvironment to release the loaded α-TOS. Therefore, the HA/α-TOS@ZIF-8 nanoplatform has been achieved as a tumor-specific and on-demand drug delivery system, which improved the treatment efficiency.