Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy ha...Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy has shown potential to inhibit recurrence and metastasis,the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments.The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells(TIDCs)which leads to an inferior immune response to distant tumor growth and metastasis.Herein,an antigen-capturing nanoplatform,whose surface was modified with mannose as a targeting ligand,was constructed for co-delivering tumor-associated antigens(TAAs)and m6A demethylases inhibitor(i.e.,fat mass and obesity asso-ciated gene(FTO)inhibitor)into TIDCs.In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells(DCs)maturation,improves tumor infiltration of effector T cells and generates immune memory,which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis.Therefore,the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.展开更多
Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macr...Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity,which leads to microflora disturbance,destructive periodontal inflammation and alveolar bone loss eventually.Here,an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages(named ex-situ macrophages hereafter)and a complement C5a receptor antagonist(C5A)to the gingival crevice.Through appropriately tuning the hydrogel stiffness,the phagocytic activity of these macrophages is greatly enhanced,reaching an optimal performance at the elastic modulus of 106 kPa.Meanwhile,C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages.Besides,the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche,which contributes to the alleviated periodontal inflammation and attenuated bone loss as well.This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells,which is expected to find wide applications even beyond periodontitis treatment.展开更多
Theranostic nanodrugs combining magnetic resonance imaging(MRI)and cancer therapy have attracted extensive interest in cancer diagnosis and treatment.Herein,a manganese(Mn)-doped mesoporous polydopamine(Mn-MPDA)nanodr...Theranostic nanodrugs combining magnetic resonance imaging(MRI)and cancer therapy have attracted extensive interest in cancer diagnosis and treatment.Herein,a manganese(Mn)-doped mesoporous polydopamine(Mn-MPDA)nanodrug incorporating the nitric oxide(NO)prodrug BNN6 and immune agonist R848 was developed.The nanodrug responded to the H^(+)and glutathione being enriched in tumor microenvironment to release R848 and Mn^(2+).The abundant Mn^(2+)produced through a Fenton-like reaction enabled a highly sensitive T1-T2 dual-mode MRI for monitoring the tumor accumulation process of the nanodrug,based on which an MRI-guided laser irradiation was achieved to trigger the NO gas therapy.Meanwhile,R848 induced the re-polarization of tumor-promoting M2-like macrophage to a tumoricidal M1 phenotype.Consequently,a potent synergistic antitumor effect was realized in mice bearing subcutaneous 4T1 breast cancer,which manifested the great promise of this multifunctional nanoplatform in cancer treatment.展开更多
The dense desmoplastic stroma and immunosuppressive microenvironment of pancreatic cancer hinder the penetration of drugs and induce a considerable resistance to conventional chemoradiotherapy. Although nanomedicine h...The dense desmoplastic stroma and immunosuppressive microenvironment of pancreatic cancer hinder the penetration of drugs and induce a considerable resistance to conventional chemoradiotherapy. Although nanomedicine has recently shown attractive potential in cancer immunotherapy, it remains a great challenge to achieve efficient drug delivery and potent immune activation.Here, a stimuli-responsive nanosystem, comprising superparamagnetic iron oxide nanocrystals and nitric oxide(NO) donors,was developed for in-situ triggered catalytic cascade reaction to produce abundant free radicals and remodel the anti-tumor immunity. The nanosystem was activated in the tumor microenvironment to produce NO which dilated the tumor vasculature for efficient drug delivery, and the iron oxide nanocrystals catalyzed the reaction of NO to generate reactive oxygen-nitrogen species(RONS) with high cytotoxicity. Moreover, owing to the catalytic cascade reactions mediated by the nanosystem, the tumor associated macrophages(TAMs) were converted to a proinflammatory M1 phenotype and tumor infiltration of effector T cells was promoted to result in potent anti-tumor immunotherapy which could be readily monitored with magnetic resonance imaging(MRI).展开更多
RNA interference(RNAi),known for the highly efficient targeted gene silencing,has been demonstrated to be a promising means for cancer treatment.Meanwhile,an effective approach for siRNA delivery is urgently needed to...RNA interference(RNAi),known for the highly efficient targeted gene silencing,has been demonstrated to be a promising means for cancer treatment.Meanwhile,an effective approach for siRNA delivery is urgently needed to meet the needs for its clinical application.Herein,we constructed a polymeric vector labeled with superparamagnetic iron oxide(SPIO)for magnetic resonance imaging(MRI)visible siRNA delivery.EGFR antibody was also modified to the surface of nanodrug to enhance the delivery effect.Our results showed that the vector exhibited great siRNA complexation ability and mediated an increased endocytosis of siRNA without obvious cytotoxicity.Besides,both in vitro and in vivo studies evidenced the vector could effectively deliver siRNA into tumor cells,exert highly interfering effect,and show potent MR imaging capacity.The study provides a promising MRI-visible and EGFR targeting delivery system to improve RNAi efficacy for cancer therapy.展开更多
基金National Natural Science Foundation of China(51933011,31971296,52173125,82102194,81873920,82001930)Key Areas Research and Development Program of Guangzhou(202007020006)+2 种基金Natural Science Foundation of the Guangdong Province(2021A1515010250,2020A1515111206,2021A1515111006)China Postdoctoral Science Foundation(2020M680119,2021M703763)Funding of the Southern Medical University Nanfang Hospital(2019C015).
文摘Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy has shown potential to inhibit recurrence and metastasis,the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments.The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells(TIDCs)which leads to an inferior immune response to distant tumor growth and metastasis.Herein,an antigen-capturing nanoplatform,whose surface was modified with mannose as a targeting ligand,was constructed for co-delivering tumor-associated antigens(TAAs)and m6A demethylases inhibitor(i.e.,fat mass and obesity asso-ciated gene(FTO)inhibitor)into TIDCs.In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells(DCs)maturation,improves tumor infiltration of effector T cells and generates immune memory,which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis.Therefore,the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.
基金This work was supported by the National Natural Science Foundation of China(82170987,81970963,51933011,31971296)the Natural Science Foundation of Guangdong Province(2021A1515012535)the General Scientific Research Cultivation Project of Guanghua School of Stomatology,Sun Yat-Sen University(174-2018-XMZC-0001-03-0125/D-16).
文摘Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity,which leads to microflora disturbance,destructive periodontal inflammation and alveolar bone loss eventually.Here,an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages(named ex-situ macrophages hereafter)and a complement C5a receptor antagonist(C5A)to the gingival crevice.Through appropriately tuning the hydrogel stiffness,the phagocytic activity of these macrophages is greatly enhanced,reaching an optimal performance at the elastic modulus of 106 kPa.Meanwhile,C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages.Besides,the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche,which contributes to the alleviated periodontal inflammation and attenuated bone loss as well.This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells,which is expected to find wide applications even beyond periodontitis treatment.
基金supported by the National Natural Science Foundation of China(Nos.51933011 and 31971296)the Key Areas Research and Development Program of Guangzhou(No.202007020006)+3 种基金Guangdong Basic and Applied Basic Research Foundation(No.2020A1515010523)Guangzhou Science and Technology Bureau(No.202102010181)Guangdong Provincial Key Laboratory of Sensing Technology and Biomedical Instrument(Sun Yat-sen University,No.2020B1212060077)approved by the Institutional Animal Care and Use Committee at Sun Yat-sen University(SYSU-IACUC-2021-000225).
文摘Theranostic nanodrugs combining magnetic resonance imaging(MRI)and cancer therapy have attracted extensive interest in cancer diagnosis and treatment.Herein,a manganese(Mn)-doped mesoporous polydopamine(Mn-MPDA)nanodrug incorporating the nitric oxide(NO)prodrug BNN6 and immune agonist R848 was developed.The nanodrug responded to the H^(+)and glutathione being enriched in tumor microenvironment to release R848 and Mn^(2+).The abundant Mn^(2+)produced through a Fenton-like reaction enabled a highly sensitive T1-T2 dual-mode MRI for monitoring the tumor accumulation process of the nanodrug,based on which an MRI-guided laser irradiation was achieved to trigger the NO gas therapy.Meanwhile,R848 induced the re-polarization of tumor-promoting M2-like macrophage to a tumoricidal M1 phenotype.Consequently,a potent synergistic antitumor effect was realized in mice bearing subcutaneous 4T1 breast cancer,which manifested the great promise of this multifunctional nanoplatform in cancer treatment.
基金supported by the National Natural Science Foundation of China (51933011, 31971296)the Key Areas Research and Development Program of Guangzhou (202007020006, 2019B020235001)+2 种基金the Natural Science Foundation of the Guangdong Province (2021A1515011799)the Opening Project of State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University (201922)the Science and Technology Project of Yantian District in Shenzhen City, Guangdong Province, China (20190106)。
文摘The dense desmoplastic stroma and immunosuppressive microenvironment of pancreatic cancer hinder the penetration of drugs and induce a considerable resistance to conventional chemoradiotherapy. Although nanomedicine has recently shown attractive potential in cancer immunotherapy, it remains a great challenge to achieve efficient drug delivery and potent immune activation.Here, a stimuli-responsive nanosystem, comprising superparamagnetic iron oxide nanocrystals and nitric oxide(NO) donors,was developed for in-situ triggered catalytic cascade reaction to produce abundant free radicals and remodel the anti-tumor immunity. The nanosystem was activated in the tumor microenvironment to produce NO which dilated the tumor vasculature for efficient drug delivery, and the iron oxide nanocrystals catalyzed the reaction of NO to generate reactive oxygen-nitrogen species(RONS) with high cytotoxicity. Moreover, owing to the catalytic cascade reactions mediated by the nanosystem, the tumor associated macrophages(TAMs) were converted to a proinflammatory M1 phenotype and tumor infiltration of effector T cells was promoted to result in potent anti-tumor immunotherapy which could be readily monitored with magnetic resonance imaging(MRI).
基金financially supported by the National Natural Science Foundation of China (Nos. 52173125 and 21805314)the Key Areas Research and Development Program of Guangzhou (No.202007020006)Natural Science Foundation of the Guangdong Province (No. 2021A1515010250)
文摘RNA interference(RNAi),known for the highly efficient targeted gene silencing,has been demonstrated to be a promising means for cancer treatment.Meanwhile,an effective approach for siRNA delivery is urgently needed to meet the needs for its clinical application.Herein,we constructed a polymeric vector labeled with superparamagnetic iron oxide(SPIO)for magnetic resonance imaging(MRI)visible siRNA delivery.EGFR antibody was also modified to the surface of nanodrug to enhance the delivery effect.Our results showed that the vector exhibited great siRNA complexation ability and mediated an increased endocytosis of siRNA without obvious cytotoxicity.Besides,both in vitro and in vivo studies evidenced the vector could effectively deliver siRNA into tumor cells,exert highly interfering effect,and show potent MR imaging capacity.The study provides a promising MRI-visible and EGFR targeting delivery system to improve RNAi efficacy for cancer therapy.