Cryo-self-assembled silk fibroin sponge as a biodegradable platform for enzyme-responsive delivery of exosomes

Although advances in protein assembly preparation have provided a new platform for drug delivery during tissue engineering,achieving long-term controlled exosome delivery remains a significant challenge.Diffusion-dominated exosome release using protein hydrogels results in burst release of exosomes.Here,a fibroin-based cryo-sponge was developed to provide controlled exosome release.Fibroin chains can self-assemble into silk I structures under ice-cold conditions when annealed above the glass transition temperature.Exosome release is enzyme-responsive,with rates primarily determined by enzymatic degradation of the scaffolds.In vivo experiments have demonstrated that exosomes remain in undigested sponge material for two months,superior to their retention in fibrin glue,a commonly used biomaterial in clinical practice.Fibroin cryo-sponges were implanted subcutaneously in nude mice.The exosome-containing sponge group exhibited better neovascularization and tissue ingrowth effects,demonstrating the efficacy of this exosome-encapsulating strategy by realizing sustained release and maintaining exosome bioactivity.These silk fibroin cryo-sponges containing exosomes provide a new platform for future studies of exosome therapy.

Oral colon-targeted mucoadhesive micelles with enzyme-responsive controlled release of curcumin for ulcerative colitis therapy

Although multitudinous nanoscale drug-delivery systems(DDSs)have been recommended to improve anti-ulcerative colitis(UC)outcomes,to enhance the mucoadhesion of nanosystems on the colon and specifically release the loaded drugs in response to the colon micro-environment would be critical factors.The application of curcumin(Cur),an acknowledged anti-UC phytochemical compound,for UC therapy requires more efficient nano-carriers to improve its therapeutic outcome.Herein,we developed the colon-targeted nano-micelles with mucoadhesive effect and Azo reductase-triggered drug release profiles for Cur delivery in UC treatment.Specifically,the amphiphilic block polymer containing the Azo-reductase sensitive linkage(PEG-Azo-PLGA),and catechol-modified TPGS(Cat-TPGS)were synthesized respectively.Based on the self-assembly of the mixed polymers,Cur-micelles(142.7±1.7 nm of average size,72.36%±1.54%of DEE)were obtained.Interestingly,the Cur-micelles exhibited the Azo-reductase sensitive particle dissociation and drug release,the enhanced cellular uptake and the prolonged retention on colonic mucosa,mediated by the strong mucoadhesion of catechol structure.Ultimately,Cur-micelles significantly mitigated colitis symptoms and accelerated colitis repair in DSS-treated mice by regulating the intestinal flora and the levels of pro-inflammatory factors(MPO,IL-6,IL-1β,and TNF-α)related to TLR4/MyD88/NF-κB signaling pathway.This work provides an effective drug delivery strategy for anti-UC drugs by oral administration.

Enzyme-responsive polysaccharide supramolecular nanoassembly for enhanced DNA encapsulation and controlled release

An enzyme-responsive polysaccharide supramolecular targeted nanoassembly was successfully constructed by the host-guest complexation of positively charged mono-(6-(tetraethylenepentamine)-6-deoxy)-β-cyclodextrin(TEPA-CD)with adamantane-grafted hyaluronic acid(HA-ADA).Possessing a series of positively charged polyamine chains,the obtained polysaccharide nanoassembly could serve as a biocompatible plasmid DNA(p DNA)container.More interestingly,the p DNA could be released from the nanoassembly through the enzymatic degradation of HA skeleton,which realized the controlled p DNA binding and release.Besides,the polysaccharide nanoassembly exhibited lower cytotoxicity than the commercial transfection reagents 25 k Da b PEI(PEI_(25 k)),accompanied by similar gene delivery effect.We believe that this work might present a convenient method for targeted,controlled gene delivery.

Intracellular and extracellular enzymatic responsive micelle for intelligent therapy of cancer

Recently,the incidence of cancer keeps increasing,seriously endangers human health,and has evolved into the main culprit of human death.Conventional chemotherapeutic drugs,such as paclitaxel and doxorubicin(DOX),have some disadvantages,including low therapeutic effect,poor water solubility,high toxic side effects,short blood circulation time in the body,and so on.To improve the anti-tumor effect of the drug in vivo and reduce its side effects on the body,researchers have designed and developed a variety of responsive nanocarriers.In this work,we synthesized D-α-tocopherol polyethylene glycol 3350 succinate(TPGS3350)-Gly-Pro-Leu-Gly-Val-Arg(GPLGVR)-DOX(TPD)prodrugs in response to extracellular enzymes of matrix metalloproteinase(MMP-9)in the tumor microenvironment and FA-Asp-Glu-Val-Asp(DEVD)-DOX(FPD)prodrugs responsive to intracellular enzymes of caspase-3.Then,intracellular and extracellular enzyme-responsive TPD&FPD micelles with DOX(TPD&FPD&D)were successfully prepared through dialysis method.The outer layer of TPGS3350 can prolong the blood circulation time of micelles in vivo,followed by accumulation of micelles at tumor tissue through enhanced permeability and retention(EPR)effect.The peptide of GPLGVR can be cleaved by MMP-9 enzymes to remove the outer layer of TPGS3350,exposing the targeting molecule of folate,and then the micelles are engulfed by tumor cells through folate receptor-mediated endocytosis.After entering the tumor cells,the free DOX loaded in the micelles is released,which induces tumor cell apoptosis to activate caspase-3 in the cells,cutting the peptide DEVD to accelerate the intracellular release of the DOX,which further enhances cytotoxicity to improve antitumor effect.