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Traceless photodegradable polymer cocoons for universal protein delivery and light-controlled gene editing

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Science China Chemistry 2024年第2期67卷 664-676页

作者： Huaibin Yu Meron Tsegay Kifle Lili Chen Feihong Xiong Yan Zhang Shangbang Gao Wei Hou Shuliang Chen Weining Zhao Yuzhou Wu Hubei Engineering Research Center for Biomaterials and Medical Protective Materials Hubei Key Laboratory of Bioinorganic Chemistry&Materia MedicaKey Laboratory of Material Chemistry for Energy Conversion and StorageMinistry of EducationSchool of Chemistry and Chemical EngineeringHuazhong University of Science and Technology(HUST)Wuhan430074China Zhengzhou Research Institute Harbin Institute of TechnologyZhengzhou450000China College of Life Science and Technology Huazhong University of Science and Technology(HUST)Wuhan430074China Institute of Medical Virology School of Basic Medical SciencesWuhan UniversityWuhan430071China College of Pharmacy Shenzhen Technology UniversityShenzhen518118China

Polymer conjugation was found highly valuable in clinic to improve the bioavailability of protein ***,it is still a tremendous challenge to achieve a complete release of original proteins from the conjugated hybrid under external stimulus to recover active proteins in the targeted ***,we report a general light-controlled protein delivery methodology by weaving a photodegradable polymer cocoon around proteins,which could reliably protect them from degradation in the dark while efficiently releasing them under illumination without any residual *** surface charge of the polymer shell is easily tunable to facilitate efficient cell *** versatility of this strategy is demonstrated by the delivery of the Cas9/sg RNA complex that realized light-controlled gene editing both in vitro and in vivo,and such repertoire is of particular value in regard to minimizing the off-target toxicity of CRISPR-Cas9-based gene therapy.

关键词： photodegradable polymer-protein conjugate protein delivery light control gene editing

Microfluidic one-step, aqueous synthesis of size-tunable zeolitic imidazolate framework-8 for protein delivery

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Nano Research 2023年第12期16卷 13409-13418页

作者： Wenxing Lv Ziwei Han Shaokun Dong Yanjuan Huang Jinqi Deng Chao Liu Qiang Feng Jiashu Sun Beijing Engineering Research Center for BioNanotechnology CAS Key Laboratory of Standardization and Measurement for NanotechnologyNational Center for Nanoscience and TechnologyBeijing 100190China Zhejiang Cancer Hospital Hangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhou 310022China University of Chinese Academy of Sciences Beijing 100049China Department of Pharmacology Simmons Comprehensive Cancer CenterUniversity of Texas Southwestern Medical CenterDallas 75390USA

Zeolitic imidazolate framework-8(ZIF-8)with porous structure,biocompatibility,and pH-sensitive release behavior is a promising nanoplatform for protein ***,it is still a challenging task for a practical synthesis of protein-loaded ZIF-8 *** we report an all-aqueous microfluidic reactor for one-step,rapid,and highly controlled synthesis of ZIF-8 nanoparticles with high protein loading at room *** reactor allows for an ultrafast(proteins such as bovine serum albumin(BSA)(isoelectric point(pI)=5.82),ovalbumin(OVA)(pI=4.82),or RNase A(pI=8.93)with 2-MIM,ZIF-8 nanoparticles can be synthesized with protein encapsulation efficiency over 97%.Among the nanoparticles with different sizes,25 nm ZIF-8 nanoparticles show the best performance in promoting the cellular uptake of protein *** OVA as a model protein,we demonstrate that 25 nm ZIF-8 nanoparticles significantly enhance the cytosolic delivery of antigen,as indicated by the effective activation of dendritic *** anticipate that this microfluidic synthesis of nanomaterials may advance the emerging field of cytosolic protein delivery.

关键词： microfluidics zeolitic imidazolate framework-8 nanoparticles size tunable protein delivery

Lipocoacervate,a tunable vesicle for protein delivery

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Nano Research 2024年第10期17卷 9135-9140页

作者： Chia-Wei Yeh Nathaniel Wright Chelsea Loh Nabeen Chu Yadong Wang Nancy E.and Peter C.Meinig School of Biomedical Engineering Cornell UniversityKimball Hall 290Ithaca 14853USA Human Biology Healthand Society.College of Human EcologyCornell UniversityIthaca 14853USA

Controlled delivery of proteins and other biologics is a growing medium of therapy for diseases previously *** we report a self-assembling,tunable vesicle for the controlled delivery of growth factors and *** made of heparin and a biocompatible polycation,PEAD,forms the core of the vesicle;lipids form the membrane of the *** call this vesicle lipocoacervate(LipCo),which has a high affinity for growth factors and cytokines due to *** is a tunable protein delivery *** vesicle size is controlled through polymer and salt *** functionalization enables potential for targeting capabilities with long-term storage through ***,the controlled delivery of therapeutics also avoids high toxicity to treated cells in *** we report on these key principles of LipCo assembly and design.

关键词： complex coacervate drug delivery protein delivery heparin lipid particle

Enzyme-instructed hybrid nanogel/nanofiber oligopeptide hydrogel for localized protein delivery

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Acta Pharmaceutica Sinica B 2021年第7期11卷 2070-2079页

作者： Tianyue Jiang Yudi Ma Xiao Xu Qingchun Ji Mingxing Feng Cheng Cheng Yang Feng Bingfang He Ran Mo School of Pharmaceutical Sciences Nanjing Tech UniversityNanjing 211816China State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Advanced Pharmaceuticals and BiomaterialsChina Pharmaceutical UniversityNanjing 210009China

Enzyme-catalysis self-assembled oligopeptide hydrogel holds great interest in drug delivery,which has merits of biocompatibility,biodegradability and mild gelation ***,its application for protein delivery is greatly limited by inevitable degradation of enzyme on the encapsulated proteins leading to loss of protein ***,for the intracellularly acted proteins,cell membrane as a primary barrier hinders the transmembrane delivery of *** internalized proteins also suffer from acidic and enzymatic degradation in endosomes and *** herein develop a proteasemanipulated hybrid nanogel/nanofiber hydrogel for localized delivery of intracellularly acted *** embedded polymeric nanogels(CytoC/aNGs)preserve activity of cytochrome c(CytoC)that is an intracellular activator for cell apoptosis as a model protein against proteolysis,and do not affect the gelation properties of the protease-catalysis assembled *** injectable hydrogel(CytoC/aNGs/Gel)serves as a reservoir to enhance intratumoral retention and realize sustainable release of CytoC/*** released CytoC/aNGs increase cellular uptake of CytoC and enhance its intracellular delivery to its target site,cytoplasm,resulting in favorable apoptosis-inducing and cytotoxic *** show that a single local administration of CytoC/aNGs/Gel efficiently inhibit the tumor growth in the breast tumor mouse model.

关键词： protein delivery Oligopeptide hydrogel Nanogel Enzymatic catalysis Cytochrome c Apoptosis Local administration Cancer therapy

Study the lipidoid nanoparticle mediated genome editing protein delivery using 3D intestinal tissue model

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Bioactive Materials 2021年第11期6卷 3671-3677页

作者： Tao Yang Haobo Han Ying Chen Liu Yang Rachael Parker Yamin Li David L.Kaplan Qiaobing Xu Department of Biomedical Engineering Tufts UniversityMedfordMAUSA Department of Prosthodontics Guanghua School of StomatologyHospital of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-sen UniversityGuangzhou510055China Key Laboratory for Molecular Enzymology1nd Engineering of Ministry of Education School of Life SciencesJilin UniversityChangchun130012China

Lipid nanoparticles are promising carriers for oral drug *** bioactive cargos with intracellular targets,***-editing proteins,it is essential for the cargo and carrier to remain complexed after crossing the epithelial layer of intestine in order for the delivery system to transport the cargos inside targeted ***,limited studies have been conducted to verify the integrity of cargo/carrier nanocomplexes and their capability in facilitating cargo delivery intracellularly after the nanocomplex crossing the epithelial ***,we used a traditional 2D transwell system and a recently developed 3D tissue engineered intestine model and demonstrated the synthetic lipid nanoparticle(carrier)and protein(cargo)nanocomplexes are able to cross the epithelial layer and deliver the protein cargo inside the underneath *** found that the EC16-63 LNP efficiently encapsulated the GFP-Cre recombinase,penetrated the intestinal monolayer cells in both the 2D cell culture and 3D tissue models through temporarily interrupting the tight junctions between epithelial *** transporting across the intestinal epithelia,the EC16-63 and GFP-Cre recombinase nanocomplexes can enter the underneath cells to induce gene *** results suggest that the in vitro 3D intestinal tissue model is useful for identifying effective lipid nanoparticles for potential oral drug delivery.

关键词： Lipidoid nanoparticle protein delivery Oral drug delivery Genome engineering 3D tissue model

Tailoring Cationic Helical Polypeptides for Efficient Cytosolic protein delivery

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Chemical Research in Chinese Universities 2020年第1期36卷 134-138页

作者： WANG Ruijue SHENG Kai HOU Yingqin SUN Jialing LU Hua Beijing National Laboratory for Molecular Sciences Center for Soft Matter Science and EngineeringKey Laboratory of Polymer Chemistry and Physics of Ministry of EducationCollege of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871P.R.China

protein delivery is of central importance for both diagnostic and therapeutic ***,protein delivery faces challenges including poor endosomal escape and thus limited ***,we report the facile construction and screening of a small library of cationic helical polypeptides for cytosolic protein *** library is based on a random copolymer poly(γ-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}esteryl-L-glutamate)-randompoly(γ-6-chlorohexyl-L-glutamate)[P(EG3-r-ClC6)Glu],which is then modified with various pyridine derivatives and alkyl *** Cytometry,confocal laser scanning microscopy,and viability assay collaboratively identify two leading polymers,showing efficient delivery of enhanced green fluorescent protein(eGFP)and low *** finding is further validated by the cytosolic delivery of RNase A and cytochrome C(Cyt C)to HeLa cells in the viability ***,this work demonstrates that high-throughput screening is an effective and viable approach to the selection of cationic helical polypeptides for the cytosolic delivery of functional proteins.

关键词： Cationic helical polypeptide protein delivery Cytosolic protein

Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery

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Acta Pharmaceutica Sinica B 2018年第2期8卷 147-164页

作者： Angela M.Wagner Margaret P.Gran Nicholas A.Peppas McKetta Department of Chemical Engineering The University of Texas at Austin Institute for Biomaterials Drug Delivery and Regenerative Medicine The University of Texas at Austin Department of Biomedical Engineering The University of Texas at Austin Department of Pediatrics Dell Medical School The University of Texas at Austin Department of Surgery and Perioperative Care Dell Medical School The University of Texas at Austin Division of Pharmaceutics College of Pharmacy The University of Texas at Austin

Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties,therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal(GI)tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drugdelivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.

关键词： Oral delivery Hydrogels protein delivery Peptide delivery Carbohydrates Mucoadhesion

Release Model of Water-soluble Chitosan Nanoparticles for protein delivery

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Agricultural Science & Technology 2009年第3期10卷 144-147页

作者：王春孙胜玲肖惠宁何北海杨连生华南理工大学轻工与食品学院制浆与造纸国家重点实验室广东广州510640

[Objective] The experiment aimed to explore release rule of water-soluble chitosan (WSC) in vitro. [Method]The bovine serum albumin(BSA) was taken as a model protein drug and some existing release models such as Kinetics model, Gompertz model, Weibull model, Higuchi model and Logistic model were used to fit the BSA release profile from WSC carriers. [Result] Except Higuchi model and Logistic model, other models could fit BSA release profile better. [Conclusion] Gompertz two-order kinetics model could fit the release of WSC nano-particles better and model parameters had practical physical meaning.

关键词： Water-soluble chitosan Nano-particle carriers protein delivery Release model

Nanocapsules of oxalate oxidase for hyperoxaluria treatment

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Nano Research 2018年第5期11卷 2682-2688页

作者： Ming Zhao Duo Xu Di Wu James W. Whittaker Robert Terkeltaub Yunfeng Lu Department of Chemical and Biomolecular Engineering University of California Los Angeles Los Angeles CA 90095 USA Division of Environmental and Biomolecular Systems Oregon Health and Sciences University Beaverton OR 97006-8921 USA Division of Rheumatology Allergy and Immunology San Diego VA Medical Center 3350 La Jolla Village Drive San Diego CA 92161 USA

Enzyme therapeutics have great potential for the treatment of systemic disorders such as urolithiasis and nephrocalcinosis, which are caused by the excessive accumulation of oxalate. However, exogenous enzymes have short half-lives in vivo and elicit high immunogenicity, which largely limit the therapeutic outcomes. Herein, we report a delivery strategy whereby therapeutic enzymes are encapsulated within a thin zwitterionic polymer shell to form enzyme nanocapsules. The strategy is exemplified by the encapsulation of oxalate oxidase （OxO） for the treatment of hyperoxaluria, because as-synthesized OxO nanocapsules have a prolonged blood circulation half-life and elicit reduced immunogenicity. Our design of enzyme nanocapsules that enable the systemic delivery of therapeutic enzymes can be extended to various biomedical applications.

关键词： enzyme therapeutics hyperoxaluria oxalate oxidase protein delivery long circulation nanomedicine