A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury

Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.

Toward Artificial Peptide Nanocapsules

HIGHLIGHTS The formation of peptide nanocapsules is facilitated by a gradient interface,where the differential solvent concentration drives the peptides to preferentially localize and assemble.The peptide nanocapsules,characterized by their hollow structures,demonstrated potential as carriers for targeted drug delivery.1 Introduction Peptide nanocapsules are a type of nanoscale delivery system that encapsulates active substances within a shell composed of peptides,leveraging the unique properties of peptides such as biocompatibility and biodegradability[1].Historically,the development of peptide nanocapsules was inspired primordially by the natural biological processes.

Emulsion interfacial polymerization of anticancer peptides:fabricating polypeptide nanospheres with high drug-loading efficiency and enhanced anticancer activity

The development of drug delivery systems with high drug-loading efficiency, kinetic stability against dilution, as well as enhanced anticancer activity is of crucial importance to the fields of self-assembly and nanomedicine. Herein, we propose a strategy where the anticancer peptide acts as water-soluble monomer to directly participate in emulsion interfacial polymerization for fabricating polypeptide nanospheres. The constructed polypeptide nanospheres hold a high drug loading efficiency of 77%, and can be stably dispersed in highly diluted aqueous solutions. The acid-labile amide linkage in polypeptide nanospheres can be hydrolyzed in tumor acidic environments, thus releasing anticancer peptides selectively. The polypeptide nanospheres achieve significantly enhanced anticancer activity against HCT116 cells in vitro and in vivo through improved mitochondrial and membrane disruption. In addition, its side effects on normal cells can be reduced significantly. It is highly anticipated that more kinds of anticancer drug candidates or anticancer drugs can be applied to fabricate polymeric nanomedicines with improved anticancer activity through this strategy.

Emerging prospects of protein/peptide-based nanoassemblies for drug delivery and vaccine development

Proteins have been widely used in the biomedical field because of their well-defined architecture,accurate molecular weight,excellent biocompatibility and biodegradability,and easy-to-functionalization.Inspired by the wisdom of nature,increasing proteins/peptides that possess self-assembling capabilities have been explored and designed to generate nanoassemblies with unique structure and function,including spatially organized conformation,passive and active targeting,stimuli-responsiveness,and high stability.These characteristics make protein/peptide-based nanoassembly an ideal platform for drug delivery and vaccine development.In this review,we focus on recent advances in subsistent protein/peptide-based nanoassemblies,including protein nanocages,virus-like particles,self-assemblable natural proteins,and self-assemblable artificial peptides.The origin and characteristics of various protein/peptide-based assemblies and their applications in drug delivery and vaccine development are summarized.In the end,the prospects and challenges are discussed for the further development of protein/peptide-based nanoassemblies.

多肽分子自组装研究进展

多肽分子自组装是生物体中广泛存在的一种现象。通过自组装,多肽分子可结合成具有不同功能的蛋白质分子。一种有生物功能的蛋白质分子,其特定空间结构的形成实际上就是其组成氨基酸分子中各基团组装的结果。因此,多肽分子自组装可在分子水平上进行精巧的设计,从而控制组装体的形状和结构,这在生物活性肽类药物以及生物医学材料的研制方面有着巨大的潜力。近年来,多肽分子自组装进展迅速,在模拟天然生物分子的功能、药物载体以及合成多肽药物等方面得到应用。本文仅就肽自组装系统的研究进展进行简要评述。

Multifunctional building elements for the construction of peptide drug conjugates

Engineering of smart building molecules is key basis in designing intelligent drug delivery systems.As an emerging sophisticated delivery system strategy,the powerful functions of peptide drug conjugates(PDCs)are attributed to a smart linker and multifunctional peptide domain.Peptides exhibit a wide range of functions and properties,including easy chemical synthesis and versatile modification,tunable biocompatibility,diversified self-assembled nanostructures,specific recognition/binding,and deep penetration of the cell membrane/extracellular matrix.In addition,various types of linkers enable PDCs to release drugs responsively according to the disease microen-vironment or treatment needs.Owing to these inherent advantages,PDCs have been widely explored for drug delivery.Herein,the latest developments in functional peptides and linkers commonly used to construct smart PDCs are reviewed.The purpose is to bring widespread attention to PDC design strategies and their contribution to fighting various diseases,as well as to provide guidance for research on intelligent PDC drug delivery systems.

A composite peptide-supramolecular microneedle system for melanoma immunotherapy

Despite recent advances in melanoma treatment through the use of antibody immunotherapy,the clinical benefit remains restricted by its inefficient infiltration and immunosuppression within the tumor microenvironment(TME).In addition,immunerelated adverse events(irAEs)have often occurred due to the off-target binding of therapeutic drugs to normal tissues after systematic administration.Herein,we constructed an integrated and cascaded drug delivery system for the treatment of melanoma.In addition to blocking the programmed cell death protein 1 or its ligand(PD-1/PD-L1)axis,the PD-L1 targeting peptide(FE)with spherical micelle self-assembly characteristics could also effectively encapsulate the immune adjuvant resiquimod(R848),and form a complete nano drug.FE^(R)was further integrated into tumor-responsive microneedles(MNs)to establish FE^(R)@MN and could reach the cascaded functions.FE^(R)could be sustainedly released from the MN system and disassemble into monomers,achieving PD-1/PD-L1 axis blockade whilst reprogramming the immunosuppressive TME.Notably,FE^(R)@MN permits the controllable release and retention enhancement of the targeting peptide in the TME,thus causing prolonged PD-L1 blockade effect.It is demonstrated that this synergistic treatment could efficiently inhibit melanoma growth,providing a new strategy for the combination treatment of melanoma.

Supramolecular assembly of Cp1-11 peptide and insulin for rapid-acting formulation

In order to improve the life quality of diabetic patients,it is very important to develop rapid-acting insulin formulations that can mimic the physiological meal-time secretion profile of insulin in healthy people.Although several insulin analogues have been designed to provide postprandial glycemic control,still there are some serious disadvantages.A supramolecular strategy is presented here to inhibit insulin aggregation and improve its bioactivity by using Cp1-11 peptide.As a fragment of C-peptide in proinsulin,Cp1-11 peptide was found to influence insulin oligomerization by supramolecular interactions.This work demonstrates that the Cp1-11 peptide can interact with oligomeric insulin and facilitate its disaggregation into the physiologically active monomeric form.Computer simulation indicates that Cp1-11 can insert into the space between the C-terminal tail and the N-terminal helix of the B-chain of insulin,causing dissociation of the insulin dimer.The supramolecular assembly of Cp1-11 and insulin can improve the bioavailability and therapeutic effect of insulin on the control of in vivo blood glucose levels.These results suggest that Cp1-11 peptide can modulate the intermolecular interaction of aggregated insulin and prevent the transition from monomeric to multimeric states,and shows great potential for the development of an effective rapid-acting strategy to treat diabetes.