Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene del...Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo.In this study,we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs(siRNA)with high interfere to Bcl2 oncogene were designed and screened.Then hyaluronic acid dialdehyde(HAD)was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles(CS-HAD NPs)to achieve CD44 targeted siRNA delivery.The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs(siRNA@CS-HAD NPs)were approximately 100 nm in size,with improved stability,high siRNA encapsulation efficiency and low cytotoxicity.CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer.Overall,a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment,which could be more conducive to clinical application due to its simple preparation and high biological safety.展开更多
A new approach is described for delivering small interfering RNA(siRNA)into cancer cells by noncovalently complexing unmodifi ed siRNA with pristine single-walled carbon nanotubes(SWCNTs).The complexes were prepared b...A new approach is described for delivering small interfering RNA(siRNA)into cancer cells by noncovalently complexing unmodifi ed siRNA with pristine single-walled carbon nanotubes(SWCNTs).The complexes were prepared by simple sonication of pristine SWCNTs in a solution of siRNA,which then served both as the cargo and as the suspending agent for the SWCNTs.When complexes containing siRNA targeted to hypoxia-inducible factor 1 alpha(HIF-1)were added to cells growing in serum containing culture media,there was strong specific inhibition of cellular HIF-1 activity.The ability to obtain a biological response to SWCNT/siRNA complexes was seen in a wide variety of cancer cell types.Moreover,intratumoral administration of SWCNT-HIF-1 siRNA complexes in mice bearing MiaPaCa-2/HRE tumors signifi cantly inhibited the activity of tumor HIF-1.As elevated levels of HIF-1 are found in many human cancers and are associated with resistance to therapy and decreased patient survival,these results imply that SWCNT/siRNA complexes may have value as therapeutic agents.展开更多
The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially valida...The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially validated celastrol(CEL)as an inducer of immunogenic cell death(ICD)by promoting ER stress and autophagy in colorectal cancer(CRC)cells.Subsequently,an ER-targeted strategy was posited,involving the codelivery of CEL with PD-L1 small interfering RNAs(siRNA)using KDEL peptide-modified exosomes derived from milk(KME),to enhance chemoimmunotherapy outcomes.Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway.Compared to their non-targeting counterparts,KME exhibited a significant augmentation of the CEL-induced ICD effect.Additionally,it facilitated the release of danger signaling molecules(DAMPs),thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor.Concurrently,the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression,consequently fostering the proliferation and activity of CD8^(+)T cells.Ultimately,the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo.Collectively,a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.展开更多
There is a continuing quest to rationally fabricate polymeric biomaterials with both high transfection efficiency and minimal toxicity for the emerging opportunities in small interfering RNA(siRNA)delivery.Recently,th...There is a continuing quest to rationally fabricate polymeric biomaterials with both high transfection efficiency and minimal toxicity for the emerging opportunities in small interfering RNA(siRNA)delivery.Recently,this goal was promoted highly by developing a robust and efficient strategy to facilitate polymer-mediated RNAi using natural polyphenols with multiple phenol groups that could condense siRNA effectively into negatively charged nanoparticles(NPs).Further coating of these NPs with cationic polymers of low molecular weight enabled their intracellular siRNA delivery.Inspired by the structural and functional features of natural polyphenols,we aimed to further the development of low molecular weight polycatechols as a new class of efficient and biocompatible polymers for siRNA delivery in our current study.The fabricated polycatechols have benefits of requiring only one-step fabrication toward efficient siRNA nanoformulations.Moreover,they could deliver siRNA into cells and silence target genes both in vitro and in vivo.The resulting polycatechol/siRNA formulations were also functionally competent,demonstrating a successful,profound downregulation of a proinflammatory enzyme to attenuate chronic intestinal inflammation in an intestinal injury model.This study provides a new approach in chemistry for the development of efficient synthetic polymers for therapeutic siRNA delivery.展开更多
pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microsc...pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microscopy and dynamic light scattering.The synthesis of the polymer was analyzed by^(1)H-NMR.The zeta-potential changes and cellular uptake effects of the nanocomplexes under different pH environments were investigated.The experimental results show that the surface morphology of the nanocomposite is spherical,and the average particle size is about 135 nm.As the pH value of the solution gradually decreases,the surface charge of the nanocomposite reverses from negative charge to positive charge(from-9.4 to+17.1 mV).Cellular uptake mediated by pH-responsive nanocomposite is selective for tumor cells,and the cellular uptake effect in tumor cells at pH 6.5 was approximately 3 times higher than that at pH 7.4.This pH responsive charge reversal nanocomposite has promising application prospects for gene delivery in the weak acid environment of tumors.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by severe synovial inflammation and cartilage damage.Despite great progress in RA therapy,there still lacks the drugs to completely cure RA patients.Herei...Rheumatoid arthritis(RA)is an autoimmune disease characterized by severe synovial inflammation and cartilage damage.Despite great progress in RA therapy,there still lacks the drugs to completely cure RA patients.Herein,we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA(siTNFα)as an alternative anti-inflammatory approach for RA treatment.The loaded siTNFαact as not only the gene therapeutics to inhibit TNFαproduction by macrophages in inflamed synovium,but also the editors to reprogram neutrophils to anti-inflammatory phenotypes.Leveraging the active tendency of neutrophils to inflammation,the reprogrammed siTNFα/neutrophil cytopharmaceuticals(siTNFα/TP/NEs)can rapidly migrate to the inflamed synovium,transfer the loaded siTNFαto macrophages followed by the significant reduction of TNFαexpression,and circumvent the pro-inflammatory activity of neutrophils,thus leading to the alleviated synovial inflammation and improved cartilage protection.Our work provides a promising cytopharmaceutical for RA treatment,and puts forward a living neutrophil-based gene delivery platform.展开更多
Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains cha...Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.展开更多
Emerging therapies based on localized delivery of siRNA to lungs have opened up exciting possibilities for treatment of different lung diseases.Localized delivery of siRNA to lungs has shown to result in severalfold h...Emerging therapies based on localized delivery of siRNA to lungs have opened up exciting possibilities for treatment of different lung diseases.Localized delivery of siRNA to lungs has shown to result in severalfold higher lung accumulation than systemic route,while minimizing non-specific distribution in other organs.However,to date,only 2 clinical trials have explored localized delivery of siRNA for pulmonary diseases.Here we systematically reviewed recent advances in the field of pulmonary delivery of siRNA using non-viral approaches.We firstly introduce the routes of local administration and analyze the anatomical and physiological barriers towards effective local delivery of siRNA in lungs.We then discuss current progress in pulmonary delivery of siRNA for respiratory tract infections,chronic obstructive pulmonary diseases,acute lung injury,and lung cancer,list outstanding questions,and highlight directions for future research.We expect this review to provide a comprehensive understanding of current advances in pulmonary delivery of siRNA.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
基金This study was financially supported by the National Natural Science Foundation of China(81772713,81472411,81401899,81372752)Taishan Scholar Program of Shandong Province(tsqn20161077)+4 种基金Key Research and Development Program of Shandong Province(2018GSF118197)China Postdoctoral Science Foundation(2017M622144)Qingdao Postdoctoral Application Research Project.Prof.Zhang acknowledged the support from Academy of Finland(Grant no.328933)Sigrid Juselius Foundation(Grant no.28002247K1)We thank Dr.Chang Liu fromÅbo Akademi University for giving some advice to analyze the TGA data,and Ms.Qian Wen from Biomedical Center of Qingdao University for her guidance and support of in vivo fluorescence imaging.
文摘Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo.In this study,we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs(siRNA)with high interfere to Bcl2 oncogene were designed and screened.Then hyaluronic acid dialdehyde(HAD)was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles(CS-HAD NPs)to achieve CD44 targeted siRNA delivery.The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs(siRNA@CS-HAD NPs)were approximately 100 nm in size,with improved stability,high siRNA encapsulation efficiency and low cytotoxicity.CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer.Overall,a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment,which could be more conducive to clinical application due to its simple preparation and high biological safety.
基金the M.D.Anderson Cancer Center from the NIH(CA-77204 and CA-109552)to Rice University from the Welch Foundation(C-0807)+1 种基金the NSF Center for Biological and Environmental Nanotechnology(EEC-0647452)the Alliance for NanoHealth(NASA JSC-NNJ06HC25G).
文摘A new approach is described for delivering small interfering RNA(siRNA)into cancer cells by noncovalently complexing unmodifi ed siRNA with pristine single-walled carbon nanotubes(SWCNTs).The complexes were prepared by simple sonication of pristine SWCNTs in a solution of siRNA,which then served both as the cargo and as the suspending agent for the SWCNTs.When complexes containing siRNA targeted to hypoxia-inducible factor 1 alpha(HIF-1)were added to cells growing in serum containing culture media,there was strong specific inhibition of cellular HIF-1 activity.The ability to obtain a biological response to SWCNT/siRNA complexes was seen in a wide variety of cancer cell types.Moreover,intratumoral administration of SWCNT-HIF-1 siRNA complexes in mice bearing MiaPaCa-2/HRE tumors signifi cantly inhibited the activity of tumor HIF-1.As elevated levels of HIF-1 are found in many human cancers and are associated with resistance to therapy and decreased patient survival,these results imply that SWCNT/siRNA complexes may have value as therapeutic agents.
基金the financial support from the National Science Fund of Distinguished Young Scholars(No.82025032,China)the National Natural Science Foundation of China(No.82073773,China)+5 种基金the Key Research Program of Chinese Academy of Sciences(No.ZDBS-ZRKJZ-TLC005,China)the"Open Competition to Select the Best Candidates"Key Technology Program for Nucleic Acid Drugs of NCTIB(No.NCTIB2022HS01006,China)Young Elite Scientists Sponsorship Program by CAST(No.2022QNRC001,China)Shanghai Action Plan for Science,Technology,and Innovation(No.23HC1401200,China)Shanghai Post-doctoral Excellence Program(No.2022693,China)Shanghai Institute of Materia Medica,Chinese Academy of Sciences(No.SIMM0220232001,China).
文摘The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially validated celastrol(CEL)as an inducer of immunogenic cell death(ICD)by promoting ER stress and autophagy in colorectal cancer(CRC)cells.Subsequently,an ER-targeted strategy was posited,involving the codelivery of CEL with PD-L1 small interfering RNAs(siRNA)using KDEL peptide-modified exosomes derived from milk(KME),to enhance chemoimmunotherapy outcomes.Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway.Compared to their non-targeting counterparts,KME exhibited a significant augmentation of the CEL-induced ICD effect.Additionally,it facilitated the release of danger signaling molecules(DAMPs),thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor.Concurrently,the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression,consequently fostering the proliferation and activity of CD8^(+)T cells.Ultimately,the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo.Collectively,a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.
基金supported by the National Key R&D Program of China,Synthetic Biology Research(no.2019YFA0904500)the National Natural Science Foundation of China(nos.21725402 and 21774079)+1 种基金the Shanghai Municipal Science and Technology Commission(no.17XD1401600)the Guangdong Innovative and Entrepreneurial Research Team Program(no.2016ZT06C322).
文摘There is a continuing quest to rationally fabricate polymeric biomaterials with both high transfection efficiency and minimal toxicity for the emerging opportunities in small interfering RNA(siRNA)delivery.Recently,this goal was promoted highly by developing a robust and efficient strategy to facilitate polymer-mediated RNAi using natural polyphenols with multiple phenol groups that could condense siRNA effectively into negatively charged nanoparticles(NPs).Further coating of these NPs with cationic polymers of low molecular weight enabled their intracellular siRNA delivery.Inspired by the structural and functional features of natural polyphenols,we aimed to further the development of low molecular weight polycatechols as a new class of efficient and biocompatible polymers for siRNA delivery in our current study.The fabricated polycatechols have benefits of requiring only one-step fabrication toward efficient siRNA nanoformulations.Moreover,they could deliver siRNA into cells and silence target genes both in vitro and in vivo.The resulting polycatechol/siRNA formulations were also functionally competent,demonstrating a successful,profound downregulation of a proinflammatory enzyme to attenuate chronic intestinal inflammation in an intestinal injury model.This study provides a new approach in chemistry for the development of efficient synthetic polymers for therapeutic siRNA delivery.
基金Funded by the National Key R&D Program of China(No.2023YFC2412300)the Natural Science Foundation of Hubei Province(No.2022CFB386)the National Natural Science Foundation of China(No.52073222)。
文摘pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microscopy and dynamic light scattering.The synthesis of the polymer was analyzed by^(1)H-NMR.The zeta-potential changes and cellular uptake effects of the nanocomplexes under different pH environments were investigated.The experimental results show that the surface morphology of the nanocomposite is spherical,and the average particle size is about 135 nm.As the pH value of the solution gradually decreases,the surface charge of the nanocomposite reverses from negative charge to positive charge(from-9.4 to+17.1 mV).Cellular uptake mediated by pH-responsive nanocomposite is selective for tumor cells,and the cellular uptake effect in tumor cells at pH 6.5 was approximately 3 times higher than that at pH 7.4.This pH responsive charge reversal nanocomposite has promising application prospects for gene delivery in the weak acid environment of tumors.
基金supported by the National Natural Science Foundation of China(81930099,82073785,82130102,92159304,81773664)the Natural Science Foundation of Jiangsu Province(BK20212011,China)+3 种基金“Double First-Class”University project(CPU2018GY47,China)111 Project from the Ministry of Education of Chinathe State Administration of Foreign Expert Affairs of China(No.111-2-07,B17047,China)the Open Project of State Key Laboratory of Natural Medicines(No.SKLNMZZ202223,China)。
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by severe synovial inflammation and cartilage damage.Despite great progress in RA therapy,there still lacks the drugs to completely cure RA patients.Herein,we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA(siTNFα)as an alternative anti-inflammatory approach for RA treatment.The loaded siTNFαact as not only the gene therapeutics to inhibit TNFαproduction by macrophages in inflamed synovium,but also the editors to reprogram neutrophils to anti-inflammatory phenotypes.Leveraging the active tendency of neutrophils to inflammation,the reprogrammed siTNFα/neutrophil cytopharmaceuticals(siTNFα/TP/NEs)can rapidly migrate to the inflamed synovium,transfer the loaded siTNFαto macrophages followed by the significant reduction of TNFαexpression,and circumvent the pro-inflammatory activity of neutrophils,thus leading to the alleviated synovial inflammation and improved cartilage protection.Our work provides a promising cytopharmaceutical for RA treatment,and puts forward a living neutrophil-based gene delivery platform.
基金financially supported by the National Key R&D Program of China(No.2021YFA0909900).
文摘Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.
基金funding support from Department of Defense(Award Number:W81XWH-21-1-0048,USA)Department of Anesthesiology,Perioperative and Pain Medicine at the Brigham and Women's Hospital(USA)。
文摘Emerging therapies based on localized delivery of siRNA to lungs have opened up exciting possibilities for treatment of different lung diseases.Localized delivery of siRNA to lungs has shown to result in severalfold higher lung accumulation than systemic route,while minimizing non-specific distribution in other organs.However,to date,only 2 clinical trials have explored localized delivery of siRNA for pulmonary diseases.Here we systematically reviewed recent advances in the field of pulmonary delivery of siRNA using non-viral approaches.We firstly introduce the routes of local administration and analyze the anatomical and physiological barriers towards effective local delivery of siRNA in lungs.We then discuss current progress in pulmonary delivery of siRNA for respiratory tract infections,chronic obstructive pulmonary diseases,acute lung injury,and lung cancer,list outstanding questions,and highlight directions for future research.We expect this review to provide a comprehensive understanding of current advances in pulmonary delivery of siRNA.
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.
