The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circum...The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circumvent this challenge,the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results.In addition,the encapsulation of the drugs in lipid-based nanocarriers,such as solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs)or nanoemulsions(NEs),can improve nose-to-brain transport by increasing the bioavailability and site-specifc delivery.This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers(SLNs,NLCs and NEs)for nose-to-brain delivery.Based on the literature available from the past two years,we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration.The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out.Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear,it appears that the intranasal route together with the use of NLCs,SLNs or NEs is advantageous for targeting drugs to the brain.These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs,so they are expected to be approved by regulatory authorities in the coming years.展开更多
Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic ...Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.展开更多
We summarize the most important advances in RNA delivery and nanomedicine.We describe lipid nanoparticle-based RNA therapeutics and the impacts on the development of novel drugs.The fundamental properties of the key R...We summarize the most important advances in RNA delivery and nanomedicine.We describe lipid nanoparticle-based RNA therapeutics and the impacts on the development of novel drugs.The fundamental properties of the key RNA members are described.We introduced recent advances in the nanoparticles to deliver RNA to defined targets,with a focus on lipid nanoparticles(LNPs).We review recent advances in biomedical therapy based on RNA drug delivery and state-of-the-art RNA application platforms,including the treatment of different types of cancer.This review presents an overview of current LNPs based RNA therapies in cancer treatment and provides deep insight into the development of future nanomedicines sophisticatedly combining the unparalleled functions of RNA therapeutics and nanotechnology.展开更多
Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, in...Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.展开更多
This study aimed to prepare poly(D, L-lactic-co-glycolic acid) microspheres(PLGA-Ms)by a modified solid-in-oil-in-water(S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst ...This study aimed to prepare poly(D, L-lactic-co-glycolic acid) microspheres(PLGA-Ms)by a modified solid-in-oil-in-water(S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatideencapsulated lecithin nanoparticles(Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles(Ex-NPs) via the alcohol injection method,followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water(W/O/W) technique(Ex-PLGA-Ms), Ex-NPs-PLGAMs showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity.In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve(AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.展开更多
Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects...Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects.In order to avoid these drawbacks,lipid-film-coated Prussian blue nanoparticles(PB NPs)with hyaluronan(HA)modification was used for Apa loading to improve its solubility and targeting ability.Furthermore,anti-tumor compound of gamabufotalin(CS-6)was selected as a partner of Apawith reducing dosage for combinational gastric therapy.Thus,HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue.In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor(VEGFR)and matrix metalloproteinase-9(MMP-9).In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects.In summary,we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer(GC)therapy.展开更多
Critical-sized bone defects caused by traumatic fractures,tumour resection and congenital malformation are unlikely to heal spontaneously.Bone tissue engineering is a promising strategy aimed at developing in vitro re...Critical-sized bone defects caused by traumatic fractures,tumour resection and congenital malformation are unlikely to heal spontaneously.Bone tissue engineering is a promising strategy aimed at developing in vitro replacements for bone transplantation and overcoming the limitations of natural bone grafts.In this study,we developed an innovative bone engineering scaffold based on gelatin methacrylate(GelMA)hydrogel,obtained via a two-step procedure:first,solid lipid nanoparticles(SLNs)were loaded with resveratrol(Res),a drug that can promote osteogenic differentiation and bone formation;these particles were then encapsulated at different concentrations(0.01%,0.02%,0.04%and 0.08%)in GelMA to obtain the final Res-SLNs/GelMA scaffolds.The effects of these scaffolds on osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and bone regeneration in rat cranial defects were evaluated using various characterization assays.Our in vitro and in vivo investigations demonstrated that the different Res-SLNs/GelMA scaffolds improved the osteogenic differentiation of BMSCs,with the ideally slow and steady release of Res;the optimal scaffold was 0.02 Res-SLNs/GelMA.Therefore,the 0.02 Res-SLNs/GelMA hydrogel is an appropriate release system for Res with good biocompatibility,osteoconduction and osteoinduction,thereby showing potential for application in bone tissue engineering.展开更多
Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonst...Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 pandemic.This study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid tumor.The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication.Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth inhibition.These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.展开更多
Evasion of apoptosis is a hallmark of cancer,attributed in part to overexpression of the antiapoptotic protein B-cell lymphoma 2(Bcl-2).In a variety of cancer types,including lymphoma,Bcl-2 is overexpressed.Therapeuti...Evasion of apoptosis is a hallmark of cancer,attributed in part to overexpression of the antiapoptotic protein B-cell lymphoma 2(Bcl-2).In a variety of cancer types,including lymphoma,Bcl-2 is overexpressed.Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy.Therefore,the development of co-delivery systems for Bcl-2 targeting agents,such as small interfering RNA(siRNA),and chemotherapeutics,such as doxorubicin(DOX),holds promise for enabling combination cancer therapies.Lipid nanoparticles(LNPs)are a clinically advanced nucleic acid delivery system with a compact structure suitable for siRNA encapsulation and delivery.Inspired by ongoing clinical trials of albumin-hitchhiking doxorubicin prodrugs,here we developed a DOX-siRNA co-delivery strategy via conjugation of doxorubicin to the surface of siRNAloaded LNPs.Our optimized LNPs enabled potent knockdown of Bcl-2 and efficient delivery of DOX into the nucleus of Burkitts'lymphoma(Raji)cells,leading to effective inhibition of tumor growth in a mouse model of lymphoma.Based on these results,our LNPs may provide a platform for the co-delivery of various nucleic acids and DOX for the development of new combination cancer therapies.展开更多
Lipid nanoparticles(LNPs)are nanocarriers composed of four lipid components and can be used for gene therapy,protein replacement,and vaccine development.However,LNPs also face several challenges,such as toxicity,immun...Lipid nanoparticles(LNPs)are nanocarriers composed of four lipid components and can be used for gene therapy,protein replacement,and vaccine development.However,LNPs also face several challenges,such as toxicity,immune activation,and low delivery efficiency.To overcome these challenges,artificial intelligence can be used to optimize the design and formulation of LNPs,as well as to predict their properties and performance.Moreover,antibody-targeted conjugation can be used to enhance the specificity and selectivity of LNPs by attaching an antibody that recognizes a specific antigen on the cell surface to LNPs.展开更多
Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the imm...Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines.Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously.When the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA translation.The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes.Immunization with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model.Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.展开更多
基金supported by Fundacao para a Ciência e a Tecnologia(FCT)(SFRH/136177/2018,Portugal)the Applied Molecular Biosciences Unit-UCIBIO which is fnanced by national funds from FCT(UIDP/04378/2020 and UIDB/04378/2020)。
文摘The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circumvent this challenge,the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results.In addition,the encapsulation of the drugs in lipid-based nanocarriers,such as solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs)or nanoemulsions(NEs),can improve nose-to-brain transport by increasing the bioavailability and site-specifc delivery.This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers(SLNs,NLCs and NEs)for nose-to-brain delivery.Based on the literature available from the past two years,we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration.The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out.Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear,it appears that the intranasal route together with the use of NLCs,SLNs or NEs is advantageous for targeting drugs to the brain.These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs,so they are expected to be approved by regulatory authorities in the coming years.
基金support from the Maximizing Investigators'Research Awards(R35GM119679,USA)and(R35GM144117,USA)from the National Institute of General Medical Sciences。
文摘Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.
基金support of the National Key Research and Development Program of China (No.2019YFC1315701)National Natural Science Foundation of China (No.22005343)+4 种基金Cancer Hospital,Chinese Academy of Medical SciencesShenzhen Center/Shenzhen Cancer Hospital Research Project (No.SZ2020ZD004,China)Shenzhen Science and Technology Program (No.KCXFZ20201221173008022,China)Sanming Project of Medicine in Shenzhen (Nos.SZSM201812062 and SZSM201612097,China)Shenzhen Key Medical Discipline Construction Fund (No.SZXK075,China)
文摘We summarize the most important advances in RNA delivery and nanomedicine.We describe lipid nanoparticle-based RNA therapeutics and the impacts on the development of novel drugs.The fundamental properties of the key RNA members are described.We introduced recent advances in the nanoparticles to deliver RNA to defined targets,with a focus on lipid nanoparticles(LNPs).We review recent advances in biomedical therapy based on RNA drug delivery and state-of-the-art RNA application platforms,including the treatment of different types of cancer.This review presents an overview of current LNPs based RNA therapies in cancer treatment and provides deep insight into the development of future nanomedicines sophisticatedly combining the unparalleled functions of RNA therapeutics and nanotechnology.
基金funded by the Science and Technology Committee of Shanghai Municipality (Nos.19430741400, 23S11901500,23ZR1413100, and 21430760800)the National Natural Science Foundation of China (Nos.81973247 and 82030107)。
文摘Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.
基金the China Postdoctoral Science Foundation(Grant No.2016M602442)the Science and Technology Plan Projects of Guangdong Province(Grant No.2015B020232010)+1 种基金the 111 project(Grant No.B16047)the Natural Science Fund Project of Guangdong Province(Grant No.2018A030310555,Grant No.2016A030312013)。
文摘This study aimed to prepare poly(D, L-lactic-co-glycolic acid) microspheres(PLGA-Ms)by a modified solid-in-oil-in-water(S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatideencapsulated lecithin nanoparticles(Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles(Ex-NPs) via the alcohol injection method,followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water(W/O/W) technique(Ex-PLGA-Ms), Ex-NPs-PLGAMs showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity.In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve(AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.
基金supported by Changsha Municipal Natural Science Foundation(Grant No.:kq2014265),the Construction Program of Hunan's innovative Province(CN)-High-tech Industry Science and Technology Innovation Leading Project(Project No.:2020SK2002)the Natural Science Foundation of Hunan Province(Grant No.:2023JJ40130)+1 种基金Postgraduate Scientific Research Innovation Project of Hunan Province(Project No.:CX20230317)the Changsha Platform and Talent Plan(kq2203002).
文摘Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects.In order to avoid these drawbacks,lipid-film-coated Prussian blue nanoparticles(PB NPs)with hyaluronan(HA)modification was used for Apa loading to improve its solubility and targeting ability.Furthermore,anti-tumor compound of gamabufotalin(CS-6)was selected as a partner of Apawith reducing dosage for combinational gastric therapy.Thus,HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue.In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor(VEGFR)and matrix metalloproteinase-9(MMP-9).In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects.In summary,we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer(GC)therapy.
基金supported by the Natural Science Foundation of Anhui Province(Grant No.2008085QH362)Key Program of Anhui Educational Committee(Grant No.KJ2020ZD51)+2 种基金Translational Medicine Key Projects of Bengbu Medical College(Grant Nos.BYTM2019006 and BYTM 2019012)Scientific Research Innovation Team of Bengbu Medical College(Grant No.BYKC201910)512 Talents Development Project of Bengbu Medical College(Grant Nos.by51202302 and by51202309).
文摘Critical-sized bone defects caused by traumatic fractures,tumour resection and congenital malformation are unlikely to heal spontaneously.Bone tissue engineering is a promising strategy aimed at developing in vitro replacements for bone transplantation and overcoming the limitations of natural bone grafts.In this study,we developed an innovative bone engineering scaffold based on gelatin methacrylate(GelMA)hydrogel,obtained via a two-step procedure:first,solid lipid nanoparticles(SLNs)were loaded with resveratrol(Res),a drug that can promote osteogenic differentiation and bone formation;these particles were then encapsulated at different concentrations(0.01%,0.02%,0.04%and 0.08%)in GelMA to obtain the final Res-SLNs/GelMA scaffolds.The effects of these scaffolds on osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and bone regeneration in rat cranial defects were evaluated using various characterization assays.Our in vitro and in vivo investigations demonstrated that the different Res-SLNs/GelMA scaffolds improved the osteogenic differentiation of BMSCs,with the ideally slow and steady release of Res;the optimal scaffold was 0.02 Res-SLNs/GelMA.Therefore,the 0.02 Res-SLNs/GelMA hydrogel is an appropriate release system for Res with good biocompatibility,osteoconduction and osteoinduction,thereby showing potential for application in bone tissue engineering.
基金supported by a Basic Science Research Program grant through the National Research Foundation of Korea(NRF)grants(Nos.2021R1A2C4001776,RS-2023-00218648,RS-2023-00242443,and 2023-00208913)of the Republic of Koreafunded by the Ministry of Science and ICT(MSIT)of the Republic of Korea+2 种基金a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(No.RS-2023-00266015)the KIST Institutional Program(No.2E32351-23-130)of the Republic of Korea.
文摘Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 pandemic.This study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid tumor.The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication.Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth inhibition.These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.
基金support from a US National Institutes of Health(NIH)Director's New Innovator Award(DP2 TR002776,USA)a Burroughs Wellcome Fund Career Award at the Scientific Interface(CASI)+3 种基金a grant from the American Cancer Society(129784-IRG-16-188-38-IRG,USA)the National Institutes of Health(NCI R01 CA241661,NCI R37 CA244911,and NIDDK R01 DK123049,USA)support from Polish National Agency for Academic Exchange(No.PNN/IWA/2019/00057,Poland)supported by the National Science Foundation Graduate Research Fellowship Program(NSF-GRFP)under Grant No.DGE-1845298。
文摘Evasion of apoptosis is a hallmark of cancer,attributed in part to overexpression of the antiapoptotic protein B-cell lymphoma 2(Bcl-2).In a variety of cancer types,including lymphoma,Bcl-2 is overexpressed.Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy.Therefore,the development of co-delivery systems for Bcl-2 targeting agents,such as small interfering RNA(siRNA),and chemotherapeutics,such as doxorubicin(DOX),holds promise for enabling combination cancer therapies.Lipid nanoparticles(LNPs)are a clinically advanced nucleic acid delivery system with a compact structure suitable for siRNA encapsulation and delivery.Inspired by ongoing clinical trials of albumin-hitchhiking doxorubicin prodrugs,here we developed a DOX-siRNA co-delivery strategy via conjugation of doxorubicin to the surface of siRNAloaded LNPs.Our optimized LNPs enabled potent knockdown of Bcl-2 and efficient delivery of DOX into the nucleus of Burkitts'lymphoma(Raji)cells,leading to effective inhibition of tumor growth in a mouse model of lymphoma.Based on these results,our LNPs may provide a platform for the co-delivery of various nucleic acids and DOX for the development of new combination cancer therapies.
文摘Lipid nanoparticles(LNPs)are nanocarriers composed of four lipid components and can be used for gene therapy,protein replacement,and vaccine development.However,LNPs also face several challenges,such as toxicity,immune activation,and low delivery efficiency.To overcome these challenges,artificial intelligence can be used to optimize the design and formulation of LNPs,as well as to predict their properties and performance.Moreover,antibody-targeted conjugation can be used to enhance the specificity and selectivity of LNPs by attaching an antibody that recognizes a specific antigen on the cell surface to LNPs.
基金supported by the National Key Research and Development Program of China(No.2021YFA1201102)Henan Medical Science and Technology Joint Building Program(No.SBGJ202102132)+2 种基金Henan Province Youth Talent Promoting Project(No.2022HYTP047)the National Natural Science Foundation of China(Nos.82003255,82101385 and 82073231)Key Research and Development Project of Henan Province(No.232102311224)and First-Class Clinical Medicine Discipline Construction Talents Cultivation Project of Zhengzhou University.
文摘Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines.Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously.When the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA translation.The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes.Immunization with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model.Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.
