Self-Pumping Janus Hydrogel with Aligned Channels for Accelerating Diabetic Wound Healing.

Excessive exudate secreted from diabetic wounds often results in skin overhydration, severe infections, and secondary damage upon dressing changes. However, conventional wound dressings are difficult to synchronously realize the non-maceration of wound sites and rapid exudate transport due to their random porous structure. Herein, a self-pumping Janus hydrogel with aligned channels (JHA) composed of hydrophilic poly (ethylene glycol) diacrylate (PEGDA) hydrogel layer and hydrophobic polyurethane (PU)/graphene oxide (GO)/polytetrafluoroethylene (PTFE) layer is designed to rapidly export exudate and accelerate diabetic wound healing. In the design, the ice-templating process endows the hydrophilic hydrogel layer with superior liquid transport ability and mechanical strength due to the formation of aligned channel structure. The hydrophobic layer with controlled thickness functions as an effective barrier to prevent exudate from wetting the skin surface. Experiments in diabetic rat model show that JHA can significantly promote re-epithelialization and collagen deposition, shorten the inflammation phase, and accelerate wound healing. This unique JHA dressing may have great potential for real-life usage in clinical patients.

Binding-Induced Fibrillogenesis Peptides Recognize and Block Intracellular Vimentin Skeletonization against Breast Cancer.

Life is recognized as a sophisticated self-assembling material system. Cancer involves the overexpression and improper self-assembly of proteins, such as cytoskeleton protein vimentin, an emerging target related to tumor metastasis. Herein, we design a binding-induced fibrillogenesis (BIF) peptide that in situ forms fibrous networks, blocking the improper self-assembly of vimentin against cancer. The BIF peptide can bind to vimentin and subsequently perform fibrillogenesis to form fibers on vimentin. The resultant peptide fibrous network blocks vimentin skeletonization and inhibits the migration and invasion of tumor cells. In mouse models of tumor metastasis, the volume of tumor and the number of lung metastases are markedly decreased. Moreover, the efficacy of BIF peptide (5 mg/kg) is much higher than small molecular antimetastasis drug withaferin A (5 mg/kg) as a standard, indicating that the BIF peptide shows advantages over small molecular inhibitors in blocking the intracellular protein self-assembly.

A Viscous-Biofluid Self-Pumping Organohydrogel Dressing to Accelerate Diabetic Wound Healing.

Viscous biofluids on wounds challenge conventional "water-absorbing" wound dressings in efficient drainage due to their poor fluidity, generally causing prolonged inflammation, anti-angiogenesis, and delayed wound closure. Herein, it is reported that a self-pumping organohydrogel dressing (SPD) with aligned hydrated hydrogel channels, prepared by a three-dimensional-templated wetting-enabled-transfer (3D-WET) polymerization process, can efficiently drain viscous fluids and accelerate diabetic wound healing. The asymmetric wettability of the hydrophobic-hydrophilic layers and aligned hydrated hydrogel channels enable unidirectional and efficient drainage of viscous fluids away from the wounds, preventing their overhydration and inflammatory stimulation. The organogel layer can adhere onto the skin around the wounds but can be easily detached from the wet wound area, avoiding secondary trauma to the newly formed tissues. Taking a diabetic rat model as an example, the SPD can significantly downregulate the inflammation response by ≈70.8%, enhance the dermal remodeling by ≈14.3%, and shorten wound closure time by about 1/3 compared with the commercial dressing (3M, Tegaderm hydrocolloid thin dressing). This study sheds light on the development of the next generation of functional dressings for chronic wounds involving viscous biofluids.

Heterogeneous Organohydrogel Toward Automated and Interference-Free Gradient Feeding of Drugs in Cell Screening.

Cell-based microarrays are widely used in the fields of drug discovery and toxicology. Precise gradient generation and automated drug feeding are essential for high-throughput screening of live cells in tiny droplets. However, most existing technologies either require sophisticated robotic equipment or cause mechanical/physiological interference with cells. Here, a heterogeneous organohydrogel is presented for automated gradient drug feeding, while ensuring minimal interference with cells. The heterogeneous organohydrogel comprises three crucial components. The bottom surface can automatically generate gradients functioning as a gradient generator, the organohydrogel bulk allows unidirectional transport of drugs without backflow, and the top surface with hydrophilic arrays can firmly anchor the cell-based droplet array to evaluate the concentration-dependent bioeffects of drugs accurately. Such a unique structure enables universal screening of different cell types and drugs dissolved in different solvents, requiring neither additional accessories nor arduous drug functionalization. The heterogeneous organohydrogel with unprecedented automation and non-interference possesses the enormous potential to be a next-generation platform for drug screening.

An enhanced fractal self-pumping dressing with continuous drainage for accelerated burn wound healing.

Massive exudates oversecreted from burn wounds always delay the healing process, accompanied by undesired adhesion, continuous inflammation, and high infection risk. Conventional dressings with limited draining ability cannot effectively remove the excessive exudates but constrain them in the wetted dressings immersing the wound bed. Herein, we fabricate an enhanced fractal self-pumping dressing by floating and accumulating hollow glass microspheres in the hydrogel precursor, that can continuously drain water at a non-declining high speed and effectively promote burn wound healing. Small hollow glass microspheres can split the fractal microchannels into smaller ones with higher fractal dimensions, resulting in higher absorption efficiency. In an in vivo burn wound model on the dorsum of murine, the enhanced fractal self-pumping dressing can significantly reduce the appearance of the wound area and alleviate tissue edema along the healing process. This study sheds light on designing high-efficiency and continuous-draining dressings for clinical applications.

A Rapid Self-Pumping Organohydrogel Dressing with Hydrophilic Fractal Microchannels to Promote Burn Wound Healing.

Burn wounds pose great challenges for conventional dressings because massive exudates oversecreted from swollen tissues and blisters seriously delay wound healing. Herein, a self-pumping organohydrogel dressing with hydrophilic fractal microchannels is reported that can rapidly drain excessive exudates with ≈30 times enhancement in efficiency compared with the pure hydrogel, and effectively promote burn wound healing. A creaming-assistant emulsion interfacial polymerization approach is proposed to create the hydrophilic fractal hydrogel microchannels in the self-pumping organohydrogel through a dynamic floating-colliding-coalescing process of organogel precursor droplets. In a murine burn wound model, the rapid self-pumping organohydrogel dressings can markedly reduce dermal cavity by ≈42.5%, accelerate blood vessel regeneration by ≈6.6 times, and hair follicle regeneration by ≈13.5 times, compared with the commercial dressing (Tegaderm). This study paves an avenue for designing high-performance functional burn wound dressings.

In situ self-assembled peptide enables effective cancer immunotherapy by blockage of CD47.

Treatment of late-stage lung cancer has witnessed limited advances. In contrast to the tremendous efforts toward improving adaptive immunity, approaches to modulating innate immunity are relatively immature. As important innate immune cells, tumor-associated macrophages (TAMs) account for a substantial fraction of tumor-infiltrating lymphocytes, which not only reverses the immune-suppressive tumor microenvironment but also facilitates an adaptive immune response. In this study, we developed a tumor-specific MMP-2-responsive CD47 blockage (TMCB) strategy to enable effective cancer immunotherapy. Briefly, the matrix metalloproteinase-2 (MMP-2)-responsive self-assembly peptide specifically recognizes CD47, which is highly expressed in lung tumor cells. Second, the MMP-2-responsive self-assembly peptide is efficiently cleaved by MMP-2, which is overexpressed in the tumor microenvironment. Finally, the generated residual peptide naturally self-assembles into peptide-based nanofibers. The in situ constructed nanofibers inhibit the canonical CD47 "Do not eat me" signal expressed on tumor cells to promote phagocytosis of tumor cells by macrophages, which further induces effective antigen presentation and initiates T cell-mediated adaptive immune responses to inhibit tumor growth. Thus, we described a peptide-based TMCB strategy that induces both innate and adaptive immune systems to inhibit tumor growth.

OGA activated glycopeptide-based nano-activator to activate PKM2 tetramerization for switching catabolic pathways and sensitizing chemotherapy resistance.

Tumor cells intensively engage in metabolic reprogramming for enhancing the availability of glycolytic metabolites and support cell proliferation. As the most important rate-limiting enzyme in aerobic glycolysis, activating the pyruvate kinase muscle isoform 2 (PKM2) from dimers to tetramers has become a key tumor chemotherapy method to control glucose metabolism. Herein, we developed a glycopeptide-based PKM2 nano-activator, which could induce the tetramerization of PKM2 based on serine bonding to Domain C of PKM2. The bound and trapped PKM2 tetramers significantly hindered glycolytic intermediates, prevented the nucleus translocation of dimeric PKM2, and ultimately inhibited the proliferation, chemoresistance and metastasis of tumor. The glycopeptide assembled into nanoparticles under aqueous conditions and in the circulation, which in situ transformed into PKM2 nano-activator with nanofibrillar structure after specifically activated by O-GlcNAcase recognition upregulated in a wide range of human tumors. Moreover, the glycopeptide-based PKM2 nano-activator successfully accumulated at the tumor sites and boosted the chemo-drug sensitivity against prostate and breast cancers. Attributed to these intriguing results, the newly developed glycopeptide-based PKM2 nano-activator can be envisioned a promising candidate for the treatment of tumors by switching catabolic pathways.

A Polyvalent Peptide CD40 Nanoagonist for Targeted Modulation of Dendritic Cells and Amplified Cancer Immunotherapy.

Targeted immunomodulation through biomolecule-based nanostructures, especially to dendritic cells (DCs), holds great promise for effective cancer therapy. However, construction of high-performance agonist by mimicking natural ligand to activate immune cell signaling is a great challenge so far. Here, a peptide-based nanoagonist toward CD40 (PVA-CD40) with preorganized interfacial topological structure that activates lymph node DCs efficiently and persistently, achieving amplified immune therapeutic efficacy is described. The on-site fabrication of PVA-CD40 is realized through the click conjugation of two functional peptides including the "CD40 anchoring arm" and the "assembly-driving motor." The resultant polyvalent interface rapidly triggers the receptor oligomerization and downstream signaling. Strikingly, one shot administration of PVA-CD40 elicits maturation period of DCs up to 2.3-fold comparing to that of CD40 antibody. Finally, combining the PVA-CD40 with anti-PD-1 antibody results in subsequent inhibition of tumor growth in both B16F10 and 4T1 mice tumor models with survival rate up to 37%, while none of the mice survives in the clinically relevant CD40 mAb and anti-PD-1 combination-treated group. It is envisioned that the fabrication of antibody-like superstructures in vivo provides an efficient platform for modulating the duration of immune response to achieve optimal therapeutic efficacy.

Nickel-Catcher-Doped Zwitterionic Hydrogel Coating on Nickel-Titanium Alloy Toward Capture and Detection of Nickel Ions.

Nickel-titanium (NiTi) alloys show broad applicability in biomedical fields. However, the unexpected aggregation of bacteria and the corrosion of body fluid on NiTi-based medical devices often lead to the leakage of nickel ions, resulting in inevitable allergic and cytotoxic activities. Therefore, the capture and detection of nickel ions are important to avoid serious adverse reactions caused by NiTi-based medical devices. Herein, we presented a nickel ion capture strategy by the combination of zwitterionic hydrogels as anti-bacteria layers and carbon disulfide (CS2) components as nickel-catchers (Ni-catchers). On the one hand, the hydration layer of zwitterionic hydrogel can efficiently inhibit bacteria adhesion and reduce nickel ions leakage from NiTi corrosion. On the other hand, Ni-catchers can capture leaked nickel ions from NiTi alloy actively by chelation reaction. Therefore, this strategy shows great capabilities in resisting bacteria adhesion and capturing nickel ions, providing the potential possibility for the detection of nickel ion leakage for implantable biomedical materials and devices.

Click Reaction-Assisted Peptide Immune Checkpoint Blockade for Solid Tumor Treatment.

One of the major challenges of immune checkpoint blockade (ICB) is the poor penetration of antibody for solid tumor treatment. Herein, peptides with deeper penetration capability are used to develop a click reaction-assisted peptide immune checkpoint blockade (CRICB) strategy that could in situ construct assemblies, enabling enhanced accumulation and prolonged PD-L1 occupancy, ultimately realizing high-performance tumor inhibition. First, the free DBCO-modified targeting peptide (TP) efficiently recognizes and binds PD-L1 in a deep solid tumor. Upon a reagent-free click reaction with a subsequently introduced azide-tethered assembled peptide (AP), the click reaction results in spontaneous self-aggregation in situ with enhanced accumulation and prolonged occupancy. In addition, the penetration of TP-AP (121.2 ± 15.5 µm) is significantly enhanced compared with that of an antibody (19.9 ± 5.6 µm) in a solid tumor tissue. More importantly, significant immunotherapy effects and negligible side effects are observed in 4T1 and CT26 tumor-bearing mice models treated with TP-AP, suggesting the high-performance tumor inhibition attributed to the CRICB strategy. In summary, this CRICB strategy manifest the preferable effects of immune checkpoint blockade, thereby extending the biomedical application of assembling peptides.

A Near-Infrared Peptide Probe with Tumor-Specific Excretion-Retarded Effect for Image-Guided Surgery of Renal Cell Carcinoma.

Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvß3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.