Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and po...Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.展开更多
Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemo...Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin(RAP) into 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-MPTX used in combination provided enhanced efficacy through induction of both apoptosis-and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.展开更多
Nanomedicines employ multiple endocytic pathways to enter cells.Their following fate is interesting,but it is not sufficient understood currently.This review introduces the endocytic pathways,presents new technologies...Nanomedicines employ multiple endocytic pathways to enter cells.Their following fate is interesting,but it is not sufficient understood currently.This review introduces the endocytic pathways,presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection.In addition,some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end.This review may provide new thoughts for the design of novel multifunctional nanomedicines.展开更多
Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment(TME)leading to failure of immune response.Numerous therapeutic strategies in...Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment(TME)leading to failure of immune response.Numerous therapeutic strategies including chemotherapy,radiotherapy,photodynamic,photothermal,magnetic,chemodynamic,sonodynamic and oncolytic therapy,have been developed to induce immunogenic cell death(ICD)of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response.However,many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response.Here,we outline the current state of using nanomedicines for boosting ICD of cancer cells.Moreover,synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints,phagocytosis,macrophage polarization,tumor hypoxia,autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed.We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses.Endoplasmic reticulum localized ICD,focused ultrasound hyperthermia,cell membrane camouflaged nanomedicines,amplified reactive oxygen species(ROS)generation,metallo-immunotherapy,ion modulators and engineered bacteria are among the most innovative approaches.Various challenges,merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.展开更多
Albumin nanoparticles(ANPs)offer unique advantages for antitumor drug delivery system,including non-immunogenicity and inherent tumor-targeting capacity.At present,only a few products,such as ABRAXANE®and FYARRO™...Albumin nanoparticles(ANPs)offer unique advantages for antitumor drug delivery system,including non-immunogenicity and inherent tumor-targeting capacity.At present,only a few products,such as ABRAXANE®and FYARRO™,have been approved for clinical applications.The poor affinity of doxorubicin(DOX)for albumin,coupled with its numerous severe adverse reactions,poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX.In this study,we developed prodrugs by conjugating fatty acids of varying lengths with DOX.Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules.We synthesized five pH-sensitive doxorubicin-fatty acid prodrugs.Compared to free DOX,all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm.Additionally,DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells.Significantly,the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids,impacting their in vivo pharmacokinetics,antitumor effectiveness and tumor accumulation.This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs,and it builds a good platform for creating ANPs which prioritize high drug loading,high efficiency,and minimal side effects.展开更多
Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of RA.Nevertheless,the inadequate response to current therapies in a pr...Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of RA.Nevertheless,the inadequate response to current therapies in a proportion of patients,the systemic toxicity accompanied by longterm administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability,are still unsettled problems lying across the full remission of RA.So far,these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment.A variety of versatile nanocarriers with controllable physicochemical properties,tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment.This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance,pro-resolving therapy or regulating the immunometabolism for RA treatments.展开更多
Artemisinin(ART)resistance has been an emerging clinical problem,severely compromising antimalarial efficacy and threatening the global malaria elimination campaign.Albeit intensive studies about the molecular mechani...Artemisinin(ART)resistance has been an emerging clinical problem,severely compromising antimalarial efficacy and threatening the global malaria elimination campaign.Albeit intensive studies about the molecular mechanism for ART resistance are under way,no effective therapeutic targets for reversing resistance have been applied.Here,we explore glutathione(GSH)as a therapeutic target to develop a thermo-responsive nanoplatform to specifically co-deliver ART and GSH synthesis inhibitor(L-buthionine sulfoximine,BSO)in a sustained manner,effectively reversing ART resistance in vivo.By combining with BSO,ART exerts increased antimalarial activity with reduced half-maximal inhibitory concentration(IC50)by 7.43-fold in ART-resistant strains.This work reveals that the GSH in ART-resistant parasites can be a promising therapeutic target for reversing ART resistance,paving the way for developing drug candidates and intelligent nanomedicines in malaria therapy.展开更多
Tumor metastasis,the apex of cancer progression,poses a formidable challenge in therapeutic endeavors.Circulating tumor cells(CTCs),resilient entities originating from primary tumors or their metastases,significantly ...Tumor metastasis,the apex of cancer progression,poses a formidable challenge in therapeutic endeavors.Circulating tumor cells(CTCs),resilient entities originating from primary tumors or their metastases,significantly contribute to this process by demonstrating remarkable adaptability.They survive shear stress,resist anoikis,evade immune surveillance,and thwart chemotherapy.This comprehensive review aims to elucidate the intricate landscape of CTC formation,metastatic mechanisms,and the myriad factors influencing their behavior.Integral signaling pathways,such as integrin-related signaling,cellular autophagy,epithelial-mesenchymal transition,and interactions with platelets,are examined in detail.Furthermore,we explore the realm of precision nanomedicine design,with a specific emphasis on the anoikis‒platelet interface.This innovative approach strategically targets CTC survival mechanisms,offering promising avenues for combatting metastatic cancer with unprecedented precision and efficacy.The review underscores the indispensable role of the rational design of platelet-based nanomedicine in the pursuit of restraining CTC-driven metastasis.展开更多
Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation ene...Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.展开更多
Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolv...Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation.Herein,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) shell.Compared to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly.As a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model.Together,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.展开更多
Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases.Engineering specifically nanomedicines can be used to regul...Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases.Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019(COVID-19)infection.COVID-19 causes pulmonary embolisms,thus new therapeutic options are required to target thrombosis,as conventional treatment options are either not effective due to the complexity of the immunethrombosis pathophysiology.In this review,we discuss regulation of immune response in respiratory diseases especially COVID-19.We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles,which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases.We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways,and thus can be recommended to treat respiratory infectious diseases.展开更多
Lipid-based nanomedicines(LBNMs),including liposomes,lipid nanoparticles(LNPs)and extracellular vesicles(EVs),are recognized as one of the most clinically acceptable nano-formulations.However,the bench-to-bedside tran...Lipid-based nanomedicines(LBNMs),including liposomes,lipid nanoparticles(LNPs)and extracellular vesicles(EVs),are recognized as one of the most clinically acceptable nano-formulations.However,the bench-to-bedside translation efficiency is far from satisfactory,mainly due to the lack of in-depth understanding of their physical and biochemical attributes at the single-particle level.In this review,we first give a brief introduction of LBNMs,highlighting some milestones and related scientific and clinical achievements in the past several decades,as well as the grand challenges in the characterization of LBNMs.Next,we present an overview of each category of LB-NMs as well as the core properties that largely dictate their biological characteristics and clinical performance,such as size distribution,particle concentration,morphology,drug encapsulation and surface properties.Then,the recent applications of several analytical techniques including electron microscopy,atomic force microscopy,fluorescence microscopy,Raman microscopy,nanoparticle tracking analysis,tunable resistive pulse sensing and flow cytometry on the single-particle characterization of LBNMs are thoroughly discussed.Particularly,the com-parative advantages of the newly developed nano-flow cytometry that enables quantitative analysis of both the physical and biochemical characteristics of LBNMs smaller than 40 nm with high throughput and statistical ro-bustness are emphasized.The overall aim of this review article is to illustrate the importance,challenges and achievements associated with single-particle characterization of LBNMs.展开更多
Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the is...Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription （TAT）-presenting nanomedicine （DATAT-NP/Pt）, apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2,3-dimethylmaleic anhydride （DA） corona on the nanomedicine prevented the TAT peptide from serum. DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention （EPR） effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment （pH ~ 6.8）. The exposed TAT peptide augmented tumor retention and nuclear translocation of DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome path- ophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.展开更多
Despite great therapeutic effect of Abraxane®,complex preparation technology and unfavorable pharmacokinetics still restricted the clinical application of albumin-based paclitaxel(PTX)nanoparticles(NPs).Herein,we...Despite great therapeutic effect of Abraxane®,complex preparation technology and unfavorable pharmacokinetics still restricted the clinical application of albumin-based paclitaxel(PTX)nanoparticles(NPs).Herein,we reported that an albumin-binding prodrug,phenylboronic acid-conjugated PTX(P-PTX),can form the uniform NPs with the diameters around 100 nm with the help of albumin via simple one-step nano-precipitation method.The albumin-based nanomedicines were stabilized by the integration of a single boronic acid with PTX due to the increased affinity based on multiple intermolecular interactions.We found that albumin-based P-PTX NPs exhibited superior colloidal stability over albumin-based PTX NPs through one-step nanoprecipitation approach,achieving longer in vivo circulation time and higher concentration in tumor than those of the marketed Abraxane®.Furthermore,the albumin-based P-PTX NPs with great stability and enhanced intratumoral enrichment,increased the maximum tolerated dose of PTX,remarkably suppressed the growth of breast tumor and lung metastasis,prolonged survival of melanoma tumors-bearing mice.Such a convenient and effective system gains an insight into the impact of phenylboronic acid group on the albumin-based PTX NPs,provides potent strategy for the rational design of albumin-based antitumor nanomedicines.展开更多
Pulmonary hypertension(PH)can cause breathing difficulty,a rapid decline of exercise capacity,heart failure,eventually death of the patients.The latest epidemiological study demonstrates that PH has a much higher inci...Pulmonary hypertension(PH)can cause breathing difficulty,a rapid decline of exercise capacity,heart failure,eventually death of the patients.The latest epidemiological study demonstrates that PH has a much higher incidence than previously thought.PH is still a highly fatal disease due to the many disadvantages of the current drugs,such as short half-life,lack of targeting,potent side effects.The PH pathological features offer great opportunities for nanomedicines for PH.Recently,emerging nanomedicines demonstrated great advantages in the therapeutic effect of PH by enhancing the accumulation of drugs in PH lesion,optimizing drug efficacy,minimizing drug side effects.However,this promising field of cross-cutting research is far from being widely explored due to the huge professional barriers.To solve this problem,we provide a comprehensive review for the latest progresses of nanomedicines in the treatment of PH.Firstly,we systematical summarized the PH pathological features and the current clinical drug treatment of PH.The advantages of nanomedicines are also deeply discussed in the treatment of PH.Subsequently,we focused on the research progresses of nanomedicines in PH through three aspects:advanced nano-drug delivery system for traditional drugs and new target drugs,gene therapy-based nanomedicines,other nanomedicines for the treatment of PH.Finally,we also discussed the prospects and challenges for the clinical application of nanomedicines in PH,provided directions for the research and development of nanomedicines for PH treatment in the future.展开更多
The most common socioeconomic healthcare issues in clinical are burns,surgical incisions and other skin injuries.Skin lesion healing can be achieved with nanomedicines and other drug application techniques.This study ...The most common socioeconomic healthcare issues in clinical are burns,surgical incisions and other skin injuries.Skin lesion healing can be achieved with nanomedicines and other drug application techniques.This study developed a nano-spray based on cross-linked amorphous calcium peroxide(CaO_(2))nanoparticles of polyacrylic acid(PAA)for treating skin wounds(PAA-CaO_(2)nanoparticles).CaO_(2)serves as a‘drug’precursor,steadily and continuously releasing calcium ions(Ca2+)and hydrogen peroxide(H2O_(2))under mildly acidic conditions,while PAA-CaO_(2)nanoparticles exhibited good spray behavior in aqueous form.Tests demonstrated that PAA-CaO_(2)nanoparticles exhibited low cytotoxicity and allowed L929 cells proliferation and migration in vitro.The effectiveness of PAA-CaO_(2)nanoparticles in promoting wound healing and inhibiting bacterial growth in vivo was assessed in SD rats using full-thickness skin defect and Staphylococcus aureus(S.aureus)-infected wound models based thereon.The results revealed that PAA-CaO_(2)nanoparticles demonstrated significant advantages in both aspects.Notably,the infected rats’skin defects healed in 12 days.The benefits are linked to the functional role of Ca^(2+)coalesces with H2O_(2)as known antibacterial and healing-promoted agents.Therefore,we developed nanoscale PAA-CaO_(2)sprays to prevent bacterial development and heal skin lesions.展开更多
Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and treatment.Biomimetic nanomedicines(b NMs)are...Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and treatment.Biomimetic nanomedicines(b NMs)are moving closer to fulfilling this need,pushing back the frontier of nano-based drug delivery systems design.This review seeks to outline how these nanomedicines(NMs)might work to diagnose and treat atherosclerosis,to trace the trajectory of their development to date and in the coming years,and to provide a foundation for further discussion about atherosclerotic theranostics.展开更多
基金This study was supported by National Natural Science Foundation of China(82173762)111 Project(B18035,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,2022YFS0334).
文摘Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.
基金supported by the National Natural Science Foundation of China(81690264)Key Project from the Ministry of Science and Technology(Grant No.2018ZX09721003)Scientific Research Incubation Fund of Beijing Children’s Hospital,Capital Medical University(Grant No.GPY201711,China)
文摘Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin(RAP) into 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-MPTX used in combination provided enhanced efficacy through induction of both apoptosis-and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.
文摘Nanomedicines employ multiple endocytic pathways to enter cells.Their following fate is interesting,but it is not sufficient understood currently.This review introduces the endocytic pathways,presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection.In addition,some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end.This review may provide new thoughts for the design of novel multifunctional nanomedicines.
文摘Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment(TME)leading to failure of immune response.Numerous therapeutic strategies including chemotherapy,radiotherapy,photodynamic,photothermal,magnetic,chemodynamic,sonodynamic and oncolytic therapy,have been developed to induce immunogenic cell death(ICD)of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response.However,many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response.Here,we outline the current state of using nanomedicines for boosting ICD of cancer cells.Moreover,synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints,phagocytosis,macrophage polarization,tumor hypoxia,autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed.We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses.Endoplasmic reticulum localized ICD,focused ultrasound hyperthermia,cell membrane camouflaged nanomedicines,amplified reactive oxygen species(ROS)generation,metallo-immunotherapy,ion modulators and engineered bacteria are among the most innovative approaches.Various challenges,merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.
基金the National Key R&D Program of China(No.2022YFE0111600)National Natural Science Foundation of China(Nos.82272151 and 82204318)。
文摘Albumin nanoparticles(ANPs)offer unique advantages for antitumor drug delivery system,including non-immunogenicity and inherent tumor-targeting capacity.At present,only a few products,such as ABRAXANE®and FYARRO™,have been approved for clinical applications.The poor affinity of doxorubicin(DOX)for albumin,coupled with its numerous severe adverse reactions,poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX.In this study,we developed prodrugs by conjugating fatty acids of varying lengths with DOX.Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules.We synthesized five pH-sensitive doxorubicin-fatty acid prodrugs.Compared to free DOX,all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm.Additionally,DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells.Significantly,the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids,impacting their in vivo pharmacokinetics,antitumor effectiveness and tumor accumulation.This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs,and it builds a good platform for creating ANPs which prioritize high drug loading,high efficiency,and minimal side effects.
基金supported by the National Natural Science Foundation of China(No.82003661)。
文摘Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of RA.Nevertheless,the inadequate response to current therapies in a proportion of patients,the systemic toxicity accompanied by longterm administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability,are still unsettled problems lying across the full remission of RA.So far,these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment.A variety of versatile nanocarriers with controllable physicochemical properties,tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment.This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance,pro-resolving therapy or regulating the immunometabolism for RA treatments.
基金supported by the National Natural Science Foundation of China(Nos.81803470 and 82173767)。
文摘Artemisinin(ART)resistance has been an emerging clinical problem,severely compromising antimalarial efficacy and threatening the global malaria elimination campaign.Albeit intensive studies about the molecular mechanism for ART resistance are under way,no effective therapeutic targets for reversing resistance have been applied.Here,we explore glutathione(GSH)as a therapeutic target to develop a thermo-responsive nanoplatform to specifically co-deliver ART and GSH synthesis inhibitor(L-buthionine sulfoximine,BSO)in a sustained manner,effectively reversing ART resistance in vivo.By combining with BSO,ART exerts increased antimalarial activity with reduced half-maximal inhibitory concentration(IC50)by 7.43-fold in ART-resistant strains.This work reveals that the GSH in ART-resistant parasites can be a promising therapeutic target for reversing ART resistance,paving the way for developing drug candidates and intelligent nanomedicines in malaria therapy.
基金funded by Tianjin University of Traditional Chinese Medicine Startup Funding to Yunfei Li,and supported by Open Projects Fund of Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology,Shandong University(No.2023CCG13,China)funded by National Natural Science Foundation of China(No.82074030).
文摘Tumor metastasis,the apex of cancer progression,poses a formidable challenge in therapeutic endeavors.Circulating tumor cells(CTCs),resilient entities originating from primary tumors or their metastases,significantly contribute to this process by demonstrating remarkable adaptability.They survive shear stress,resist anoikis,evade immune surveillance,and thwart chemotherapy.This comprehensive review aims to elucidate the intricate landscape of CTC formation,metastatic mechanisms,and the myriad factors influencing their behavior.Integral signaling pathways,such as integrin-related signaling,cellular autophagy,epithelial-mesenchymal transition,and interactions with platelets,are examined in detail.Furthermore,we explore the realm of precision nanomedicine design,with a specific emphasis on the anoikis‒platelet interface.This innovative approach strategically targets CTC survival mechanisms,offering promising avenues for combatting metastatic cancer with unprecedented precision and efficacy.The review underscores the indispensable role of the rational design of platelet-based nanomedicine in the pursuit of restraining CTC-driven metastasis.
基金supported by the National Natural Science Foundation of China(No.82172186)the Zhejiang Provincial Natural Science Foundation of China(No.LY21H160030)+1 种基金the National Natural Science Foundation of China(No.82373206,No.82073332)the National Key Research and Development Program of China(No.2022YFE0107800).
文摘Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.
基金supported by Science and Technology Major Project of Liaoning(No.2019JH1/10300004,China)the National Natural Science Foundation of China(No.81773656 and 81703451)+2 种基金the Excellent Youth Science Foundation of Liaoning Province(No.2020-YQ-06,China)the China Postdoctoral Science Foundation(No.2020M670794)the Liaoning Revitalization Talents Program(No.XLYC1907129 and XLYC1808017,China)。
文摘Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation.Herein,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) shell.Compared to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly.As a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model.Together,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.
文摘Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases.Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019(COVID-19)infection.COVID-19 causes pulmonary embolisms,thus new therapeutic options are required to target thrombosis,as conventional treatment options are either not effective due to the complexity of the immunethrombosis pathophysiology.In this review,we discuss regulation of immune response in respiratory diseases especially COVID-19.We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles,which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases.We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways,and thus can be recommended to treat respiratory infectious diseases.
基金We are grateful to the National Natural Science Foundation of China(21934004,21627811)the National Key R&D Program of China(2021YFA0909400)the Natural Science Foundation of Fujian Province(2022J01329)for financial support.
文摘Lipid-based nanomedicines(LBNMs),including liposomes,lipid nanoparticles(LNPs)and extracellular vesicles(EVs),are recognized as one of the most clinically acceptable nano-formulations.However,the bench-to-bedside translation efficiency is far from satisfactory,mainly due to the lack of in-depth understanding of their physical and biochemical attributes at the single-particle level.In this review,we first give a brief introduction of LBNMs,highlighting some milestones and related scientific and clinical achievements in the past several decades,as well as the grand challenges in the characterization of LBNMs.Next,we present an overview of each category of LB-NMs as well as the core properties that largely dictate their biological characteristics and clinical performance,such as size distribution,particle concentration,morphology,drug encapsulation and surface properties.Then,the recent applications of several analytical techniques including electron microscopy,atomic force microscopy,fluorescence microscopy,Raman microscopy,nanoparticle tracking analysis,tunable resistive pulse sensing and flow cytometry on the single-particle characterization of LBNMs are thoroughly discussed.Particularly,the com-parative advantages of the newly developed nano-flow cytometry that enables quantitative analysis of both the physical and biochemical characteristics of LBNMs smaller than 40 nm with high throughput and statistical ro-bustness are emphasized.The overall aim of this review article is to illustrate the importance,challenges and achievements associated with single-particle characterization of LBNMs.
基金This work was supported by the National Key R＆D Program of China （No. 2017YFA0205600）, and the National Natural Science Foundation of China （Nos. 51773191, 51573176 and 51633008）.
文摘Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription （TAT）-presenting nanomedicine （DATAT-NP/Pt）, apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2,3-dimethylmaleic anhydride （DA） corona on the nanomedicine prevented the TAT peptide from serum. DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention （EPR） effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment （pH ~ 6.8）. The exposed TAT peptide augmented tumor retention and nuclear translocation of DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome path- ophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.
基金the National Key Research and Development Program of China(No.2021YFA0909900)the National Natural Science Foundation of China(Nos.82073777 and 81803442)+1 种基金the General Project of Liaoning Provincial Department of Education(Nos.LJKZ0927 and LJKQZ2021034)the Natural Science Foundation of Liaoning Province(No.2022-BS-157).
文摘Despite great therapeutic effect of Abraxane®,complex preparation technology and unfavorable pharmacokinetics still restricted the clinical application of albumin-based paclitaxel(PTX)nanoparticles(NPs).Herein,we reported that an albumin-binding prodrug,phenylboronic acid-conjugated PTX(P-PTX),can form the uniform NPs with the diameters around 100 nm with the help of albumin via simple one-step nano-precipitation method.The albumin-based nanomedicines were stabilized by the integration of a single boronic acid with PTX due to the increased affinity based on multiple intermolecular interactions.We found that albumin-based P-PTX NPs exhibited superior colloidal stability over albumin-based PTX NPs through one-step nanoprecipitation approach,achieving longer in vivo circulation time and higher concentration in tumor than those of the marketed Abraxane®.Furthermore,the albumin-based P-PTX NPs with great stability and enhanced intratumoral enrichment,increased the maximum tolerated dose of PTX,remarkably suppressed the growth of breast tumor and lung metastasis,prolonged survival of melanoma tumors-bearing mice.Such a convenient and effective system gains an insight into the impact of phenylboronic acid group on the albumin-based PTX NPs,provides potent strategy for the rational design of albumin-based antitumor nanomedicines.
基金the National Natural Science Foundation of China(Nos.82173817,81872872,and 21974134)the Hunan Science Fund for Distinguished Young Scholar(No.2021JJ10067,China)+1 种基金Innovation-Driven Project of Central South University(No.202045005,China)Central South University Research Programme of Advanced Interdisciplinary Studies(No.2023QYJC017).
文摘Pulmonary hypertension(PH)can cause breathing difficulty,a rapid decline of exercise capacity,heart failure,eventually death of the patients.The latest epidemiological study demonstrates that PH has a much higher incidence than previously thought.PH is still a highly fatal disease due to the many disadvantages of the current drugs,such as short half-life,lack of targeting,potent side effects.The PH pathological features offer great opportunities for nanomedicines for PH.Recently,emerging nanomedicines demonstrated great advantages in the therapeutic effect of PH by enhancing the accumulation of drugs in PH lesion,optimizing drug efficacy,minimizing drug side effects.However,this promising field of cross-cutting research is far from being widely explored due to the huge professional barriers.To solve this problem,we provide a comprehensive review for the latest progresses of nanomedicines in the treatment of PH.Firstly,we systematical summarized the PH pathological features and the current clinical drug treatment of PH.The advantages of nanomedicines are also deeply discussed in the treatment of PH.Subsequently,we focused on the research progresses of nanomedicines in PH through three aspects:advanced nano-drug delivery system for traditional drugs and new target drugs,gene therapy-based nanomedicines,other nanomedicines for the treatment of PH.Finally,we also discussed the prospects and challenges for the clinical application of nanomedicines in PH,provided directions for the research and development of nanomedicines for PH treatment in the future.
基金supported by grants from the Natural Science Foundation of Chongqing(cstc2020jcyj-msxmX0330,cstc2021jsyjyzysbA0057)the National Natural Science Foundation of China(31971242,12032007)+1 种基金the Science and Technology Innovation Project of Jinfeng Laboratory,Chongqing,China(jfkyjf202203001)the Project of Tutorial System of Medical Undergraduate in Lab Teaching&Management Center in Chongqing Medical University(LTMCMTS202107).
文摘The most common socioeconomic healthcare issues in clinical are burns,surgical incisions and other skin injuries.Skin lesion healing can be achieved with nanomedicines and other drug application techniques.This study developed a nano-spray based on cross-linked amorphous calcium peroxide(CaO_(2))nanoparticles of polyacrylic acid(PAA)for treating skin wounds(PAA-CaO_(2)nanoparticles).CaO_(2)serves as a‘drug’precursor,steadily and continuously releasing calcium ions(Ca2+)and hydrogen peroxide(H2O_(2))under mildly acidic conditions,while PAA-CaO_(2)nanoparticles exhibited good spray behavior in aqueous form.Tests demonstrated that PAA-CaO_(2)nanoparticles exhibited low cytotoxicity and allowed L929 cells proliferation and migration in vitro.The effectiveness of PAA-CaO_(2)nanoparticles in promoting wound healing and inhibiting bacterial growth in vivo was assessed in SD rats using full-thickness skin defect and Staphylococcus aureus(S.aureus)-infected wound models based thereon.The results revealed that PAA-CaO_(2)nanoparticles demonstrated significant advantages in both aspects.Notably,the infected rats’skin defects healed in 12 days.The benefits are linked to the functional role of Ca^(2+)coalesces with H2O_(2)as known antibacterial and healing-promoted agents.Therefore,we developed nanoscale PAA-CaO_(2)sprays to prevent bacterial development and heal skin lesions.
基金partially supported by grants from the National Natural Science Foundation of China (No.31971302,China)the Natural Science Foundation of Guangdong Province of China (No.2019A1515011597,China)+2 种基金the talent young scientist supporting program of China Association for Science and Technologythe Educational Commission of Guangdong Province of China Key Project (No.2020ZDZX2001,China)the joint grant between Guangzhou City and College (No.202102010106,China)。
文摘Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and treatment.Biomimetic nanomedicines(b NMs)are moving closer to fulfilling this need,pushing back the frontier of nano-based drug delivery systems design.This review seeks to outline how these nanomedicines(NMs)might work to diagnose and treat atherosclerosis,to trace the trajectory of their development to date and in the coming years,and to provide a foundation for further discussion about atherosclerotic theranostics.
