Review Article
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Open Access
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| Open AccessRediscovery of mononuclear phagocyte system blockade for nanoparticle drug delivery
Temporal blockade of the mononuclear phagocyte system is an approach to enhance the therapeutic efficiency of nanocarrier drug-delivery systems but the broad applicability is hindered by the complexity of optimisation and management of potential side effects. Here, the authors review the development of this technique and show its efficiency using meta-analysis of the published data and discuss essential features for its successful translation to clinic.
- Ivan V. Zelepukin
- , Konstantin G. Shevchenko
- & Sergey M. Deyev
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Article
| Open AccessAn antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo
Protein corona formation on the surface of liposome nanocarriers can decrease the efficiency of intracellular delivery. Here, the authors develop antifouling membrane-fusogenic liposomes for effective intracellular delivery in vivo.
- Huimin Kong
- , Chunxiong Zheng
- & Mingqiang Li
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Article
| Open AccessEnhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys
Targeted drug delivery in vivo is a complex challenge, and understanding the characteristics that define the behavior of delivery vehicles in vivo is vital for advancing delivery vehicle design. Here the authors use a library of polymeric delivery vehicles and high-throughput tools to study the structure-function relationships guiding the physiological fate of nanomedicines.
- Alexandra S. Piotrowski-Daspit
- , Laura G. Bracaglia
- & W. Mark Saltzman
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Article
| Open AccessRegulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles
Despite advances in active drug-targeting for blood-brain barrier penetration, challenges related to brain biodistribution, and drug accumulation persist. Here the authors show a molecular library design centered on cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system inspired by the neuroprotective properties of vinpocetine.
- Xufei Bian
- , Ling Yang
- & Chong Li
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Matters Arising
| Open AccessTechnical challenges of studying the impact of plasma components on the efficacy of lipid nanoparticles for vaccine and therapeutic applications
- Jens B. Simonsen
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Matters Arising
| Open AccessReply to: Technical challenges of studying the impact of plasma components on the efficacy of lipid nanoparticles for vaccine and therapeutic applications
- Kai Liu
- , Elisa Lázaro-Ibáñez
- & Alan Sabirsh
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Article
| Open AccesscircCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models
Aberrant circRNAs expression in repair cells is intricately linked to deficits in wound healing. Here, the authors engineered extracellular vesicles enriched with circCDK13 and demonstrate their ability to facilitate diabetic wound repair.
- Qilin Huang
- , Ziqiang Chu
- & Cuiping Zhang
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Article
| Open AccessTargeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix enhances gut residence time and recovery in murine colitis
In this study, the authors engineered a targeted Saccharomyces boulardii probiotic yeast platform, showing it exhibits high adherence to extracellular matrix proteins, resulting in longer gut residence, higher colon concentrations, and enhanced recovery in murine colitis.
- Mairead K. Heavey
- , Anthony Hazelton
- & Juliane Nguyen
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Article
| Open AccessExosome-coated oxygen nanobubble-laden hydrogel augments intracellular delivery of exosomes for enhanced wound healing
Challenges including hypoxia, inflammation, and inadequate exosome intracellular delivery hinder wound healing. Here, the authors show that a multifunctional exosome-coated oxygen nanobubble-laden hydrogel enhances exosome delivery and mitigates hypoxia for enhanced wound healing.
- Xiaoxue Han
- , Chaimongkol Saengow
- & Joseph Irudayaraj
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Article
| Open AccessAn all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction
Prodrugs have the potential for improving therapeutic index and expanding drug targets, but current prodrug activation strategies that are responsive to endogenous stimuli can result in unintended drug release and systemic toxicity. Here, the authors report 3-vinyl−6-oxymethyltetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling of peptides to produce bioorthogonal activable peptide-prodrug conjugates.
- Xinyu He
- , Jie Li
- & Haoxing Wu
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Article
| Open AccessCell surface patching via CXCR4-targeted nanothreads for cancer metastasis inhibition
CXCR4-targeted therapies have been proposed for the treatment of cancer metastasis. Here the authors propose a CXCR4-targeted strategy based on interactable polymer nanothreads, showing inhibition of metastasis in preclinical cancer models.
- Minglu Zhou
- , Chendong Liu
- & Lian Li
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Article
| Open AccessNanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer
In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.
- Yu-Yang Bi
- , Qiu Chen
- & Hu-Lin Jiang
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Review Article
| Open AccessArtificial cells for in vivo biomedical applications through red blood cell biomimicry
Despite the enormous progress in the field of giant lipid vesicles, their use for in vivo biomedical applications is limited. Here, the authors discuss red blood cells as inspiration for enhancing those vesicles, investigating the required cellular features and the corresponding technical hurdles.
- Jorik Waeterschoot
- , Willemien Gosselé
- & Xavier Casadevall i Solvas
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Article
| Open AccessCholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery
Cholesterol (Chol) transfer from lipid bilayer jeopardizes membrane stability and causes premature payload leakage, yielding suboptimal efficacy. Here, the authors report a Chol-modified sphingomyelin (SM) bilayer via covalently conjugating Chol to SM, which retains Chol condensing ability and improves pharmacokinetics and therapeutic delivery of various drugs in diverse disease animal models.
- Zhiren Wang
- , Wenpan Li
- & Jianqin Lu
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Article
| Open AccessEndogenous stimuli-responsive separating microneedles to inhibit hypertrophic scar through remodeling the pathological microenvironment
The treatment of hypertrophic scar (HS) is hindered by the low bioavailability of drugs and the pathological microenvironment. Here the authors report a separating microneedle drug delivery system responsive to high reactive oxygen species levels and overexpression of matrix metalloproteinases to remodel the pathological microenvironment for HS treatment.
- Zhuo-Ran Yang
- , Huinan Suo
- & Jintao Zhu
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Article
| Open AccessHigh-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models
Identifying pulmonary delivery of lipid libraries poses an obstacle for mRNA drugs. Here, the authors use a barcoded screening system to identify lung-targeting of cationic, degradable lipid-like materials for mRNA delivery and gene editing in female preclinical models.
- Lulu Xue
- , Alex G. Hamilton
- & Michael J. Mitchell
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Article
| Open AccessIn situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors
Branched ionizable lipids have aroused great interest for mRNA delivery. Here, the authors devise an in situ construction method for combinatorial synthesis of degradable branched ionizable lipids and summarize key design criteria to enable potent delivery of mRNA therapeutics and gene editors.
- Xuexiang Han
- , Junchao Xu
- & Michael J. Mitchell
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Article
| Open AccessEngineering self-deliverable ribonucleoproteins for genome editing in the brain
The delivery of CRISPR RNPs has potential advantages over other genome editing approaches, including reduced off-target editing and reduced immunogenicity. Here the authors report self-deliverable Cas9 RNPs capable of robustly editing cultured cells in vitro and the mouse brain upon direct injections.
- Kai Chen
- , Elizabeth C. Stahl
- & Jennifer A. Doudna
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Article
| Open AccessTargeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis
Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.
- Xudong Tang
- , Yangyang Shang
- & Lei Chen
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Article
| Open AccessStructural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy
Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.
- Ella N. Hoogenboezem
- , Shrusti S. Patel
- & Craig L. Duvall
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Article
| Open AccessRegulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery
The dynamic protein corona hinders the uptake of nanocarriers in desired target cell populations, limiting their bench-to-bedside translation. Here the authors reveal that the modification of hydroxyl and amino functional groups on nanovesicles can rationally regulate the composition of protein coronas to improve the efficiency of targeted drug delivery.
- Yunqiu Miao
- , Lijun Li
- & Yong Gan
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Article
| Open AccessAntiviral fibrils of self-assembled peptides with tunable compositions
In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.
- Joseph Dodd-o
- , Abhishek Roy
- & Vivek Kumar
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Article
| Open AccessRedox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy
Immune checkpoint blockade-based immunotherapy has shown limited efficacy in patients with glioblastoma (GBM). Here the authors describe the design of redox-responsive micelles for increasing the delivery of paclitaxel and anti-PD-L1 in the brain, showing improved anti-tumor immune response in preclinical GBM models.
- Zhiqi Zhang
- , Xiaoxuan Xu
- & Shenghong Ju
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Article
| Open AccessAAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation
Long-term control of therapeutic transgene expression is needed. Here the authors report a muscone-induced transgene system packaged into AAVs based on a G protein-coupled murine olfactory receptor and a synthetic cAMP-responsive promoter: they show dose- and exposure-time-dependent gene expression control in mice.
- Xin Wu
- , Yuanhuan Yu
- & Haifeng Ye
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Article
| Open AccessNon-invasive transdermal delivery of biomacromolecules with fluorocarbon-modified chitosan for melanoma immunotherapy and viral vaccines
Different approaches have been described for the transdermal delivery of drugs. Here the authors report the design of a fluorocarbon modified chitosan-based non-invasive transdermal platform for the delivery of biomacromolecules, such as viral antigens for vaccines or immune checkpoint inhibitors for melanoma immunotherapy.
- Wenjun Zhu
- , Ting Wei
- & Zhuang Liu
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Article
| Open AccessDNA mechanocapsules for programmable piconewton responsive drug delivery
The mechanical dysregulation of cells is associated with several diseases and strategies to deliver drugs based on the “mechanical phenotype” of a cell are desirable. Here, the authors design and characterize DNA mechanocapsules comprised of DNA tetrahedrons that are force responsive, and showed they can encapsulate macromolecular cargo and release it upon application of force.
- Arventh Velusamy
- , Radhika Sharma
- & Khalid Salaita
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Article
| Open AccessEnhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation
Achieving targeted drug delivery for calcified aortic valve is challenging. Here, the authors find that protease activated receptor 2 (PAR2) is up-regulated on calcified valves and develop a magnetic nanocarrier functionalized with PAR2-targeting peptide for dual-active drug delivery.
- Jinyong Chen
- , Tanchen Ren
- & Xianbao Liu
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Article
| Open AccessDigital automation of transdermal drug delivery with high spatiotemporal resolution
Microneedle patches that can actively address individual needles are challenging to realize. Here, the authors introduce a spatiotemporal on-demand patch for precise and personalized drug delivery, utilizing electrically triggered control with drug-loaded microneedles and biocompatible metallic membranes.
- Yihang Wang
- , Zeka Chen
- & Wubin Bai
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Article
| Open AccessIn vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy
The poor tumour delivery efficacy of GPX4 inhibitor has dampened its in vivo therapeutic value. Here the authors report a peptide ferriporphyrin conjugate to improve tumour penetration, endocytosis and GPX4 inhibition, synergistically enhancing its anticancer activity by ferroptosis.
- Da-Yong Hou
- , Dong-Bing Cheng
- & Hao Wang
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Article
| Open AccessInhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
A pro-tumorigenic role of iRhom1 has been described in several cancer types. Here the authors show that iRhom1 regulates sensitivity to chemotherapy and immune response, as well they report that CD44 targeting nanoparticle-mediated co-delivery of iRhom1 pre-siRNA promotes anti-tumor immune responses in preclinical cancer models.
- Zhangyi Luo
- , Yixian Huang
- & Song Li
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Article
| Open AccessAnti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy
Poor renal distribution of antibody-based drugs limits the treatment efficiency for diabetic nephropathy and causes side effects. Here, the authors prepare an antibody fragment drug conjugate, antiVEGFR2 F(ab′)2-SS31, improving renal distribution and meriting drug validation in diabetic nephropathy therapy.
- Di Liu
- , Yanling Song
- & Yongzhong Du
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Article
| Open AccessChiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease
The treatment of Parkinson’s disease (PD) is hampered by the lack of effective blood–brain barrier (BBB) traversing drugs. Here, the authors report nanozyme-integrated metal-organic frameworks with antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for PD treatment.
- Wei Jiang
- , Qing Li
- & Kelong Fan
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Article
| Open AccessNear-infrared light-triggered prodrug photolysis by one-step energy transfer
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions, but most of the photocleavable groups cannot be directly activated by near-infrared (NIR) light that features deep penetration and low phototoxicity. Here, the authors report an upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis.
- Kaiqi Long
- , Wen Lv
- & Weiping Wang
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Article
| Open AccessSystemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function
A systemically administered peptide (CARSKNKDC) that homes to injured tissues, has inherent ability to promote wound healing. Here, the authors show that this peptide binds to syndecan-4 and activates ARF6 to trigger re-epithelialisation and the naturally occurring wound repair pathway.
- Horacio Maldonado
- , Bryan D. Savage
- & Tero A. H. Järvinen
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Article
| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessLocal H2 release remodels senescence microenvironment for improved repair of injured bone
Senescence microenvironment inhibits tissue repair in elderly individuals. Here, the authors demonstrate that local H2 supply has anti-inflammation and anti-senescence effects, and develop a H2-releasing scaffold to enhance aging bone defect repair.
- Shengqiang Chen
- , Yuanman Yu
- & Qianjun He
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Article
| Open AccessNanoparticles exhibiting virus-mimic surface topology for enhanced oral delivery
The oral delivery of nano-drug delivery systems (Nano-DDS) remains challenging. Here the authors construct core–shell mesoporous silica nanoparticles with virus-like nanospikes and demonstrate the versatility of these nanoparticles as Nano-DDS to achieve efficient oral drug delivery by mimicking structural feature, chiral recognition, and gene encapsulation of viruses.
- Zhentao Sang
- , Lu Xu
- & Heran Li
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Article
| Open AccessBiofilm microenvironment triggered self-enhancing photodynamic immunomodulatory microneedle for diabetic wound therapy
The treatment of diabetic wounds tends to be hindered by complex wound environments, and the critical role of the microenvironment in the chronic diabetic wounds has not been explored for therapeutic development. Here, the authors develop a wound microenvironment-responsive microneedle bandage to achieve self-enhanced, catabolic and dynamic therapy of chronic wounds.
- Li Yang
- , Dan Zhang
- & Xiaowei Zeng
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Article
| Open AccessEnhanced pericyte-endothelial interactions through NO-boosted extracellular vesicles drive revascularization in a mouse model of ischemic injury
Treatment alternatives are not available for a significant portion of critical limb ischemia patients. Here, the authors show a strategy to engineer mesenchymal stem cells-derived extracellular vesicles to induce revascularization in mice.
- Ling Guo
- , Qiang Yang
- & Min Feng
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Article
| Open AccessSphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy
Epacadostat is a selective IDO1 inhibitor shown to promote anti-tumor immune responses in preclinical models, however it has failed in a Phase III clinical trial for treating metastatic melanoma. Here the authors design a sphingomyelin-derived nanovesicle system for epacadostat delivery with improved pharmacokinetics and anti-tumor activity when combined with a PD-1 inhibitor in melanoma preclinical models.
- Zhiren Wang
- , Wenpan Li
- & Jianqin Lu
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Article
| Open AccessAdoptive macrophage directed photodynamic therapy of multidrug-resistant bacterial infection
There is increased demand for effective, broad-spectrum treatment options against severe, multi-drug resistant bacterial infections. Here, Wang et al describe an effective photodynamic therapy based on the adoptive transfer of macrophages loaded with a lysosomal photosensitiser.
- Zehui Wang
- , Anhua Wu
- & Yi Xiao
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Article
| Open AccessPathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke
Reperfusion is a main strategy for restoring blood supply after ischemic stroke, but it induces neuroinflammation that undergoes dynamic progression, hindering the treatment of ischemic stroke. Here, the authors report a pathogenesis-adaptive nanosystem for sequential and on-demand regulation of reperfusion-induced dynamic neuroinflammation for ischemic stroke therapy.
- Di Wu
- , Jing Zhou
- & Zhong Chen
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Article
| Open AccessRational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.
- Qi Tang
- , Hassan H. Fakih
- & John E. Harris
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Article
| Open AccessCharge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism
Polymers are promising for mRNA delivery, but can have limited efficacy in hard to transfect cells. Here, the authors report charge-altering releasable transporters for improved mRNA transfection in primary T-lymphocytes and enhanced and selective protein expression in vivo.
- Zhijian Li
- , Laura Amaya
- & Paul A. Wender
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Article
| Open AccessNanosensitizer-mediated augmentation of sonodynamic therapy efficacy and antitumor immunity
The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here the authors use tin monosulfide nanoparticles as nano-sonosensitizers to overcome the stromal barrier in triple negative breast cancer and improve the efficacy of sonodynamic therapy and boost antitumor immunity.
- Yongjiang Li
- , Wei Chen
- & Wei Tao
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Article
| Open AccessAn in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases
Immune checkpoints are critical in maintaining self-tolerance and their therapeutic modulation can be achieved in autoimmune diseases. Here the authors present an in situ dual-anchoring approach that targets PD-L1 and show effects in animal models of autoimmunity.
- Shenqiang Wang
- , Ying Zhang
- & Jicheng Yu
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Article
| Open AccessAn autocatalytic multicomponent DNAzyme nanomachine for tumor-specific photothermal therapy sensitization in pancreatic cancer
Despite delivering gene-specific silencing, the use of deoxyribozymes (DNAzymes) for cancer therapy is limited by toxicity due to off-target effects. Here, the authors develop a multi-component DNAzyme, targeting both miRNA21 and HSP70, to induce tumour-specific sensitisation to photothermal therapy in preclinical models of pancreatic cancer.
- Jiaqi Yan
- , Xiaodong Ma
- & Hongbo Zhang
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Article
| Open AccessAromatized liposomes for sustained drug delivery
The development of liposome-based drug delivery systems has been hindered by the systemic toxicity and limited duration of effect due to insufficient drug loading and leakage of payload. Here the authors address these issues by designing aromatized liposomes that feature increased drug loading and slowed release compared to conventional liposomes.
- Yang Li
- , Tianjiao Ji
- & Daniel S. Kohane
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Article
| Open AccessAdaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer
There is an emerging interest in the use of mRNA therapeutics in cancer treatment, but their precise in vivo delivery remains a challenge. Here the authors develop IFN-γ mRNA-loaded small extracellular vesicles (sEVs) with CD64 overexpressed on their surface and demonstrate its efficacy in glioblastoma mouse models resistant to immunotherapy.
- Shiyan Dong
- , Xuan Liu
- & Wen Jiang