Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in...Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.展开更多
The inexhaustible heat deposit in great depths （5-10 km） is a scientific fact. Such deposit occurs around the globe. Thereby, everybody is enabled to generate autonomously clean and renewable energy, ample electrici...The inexhaustible heat deposit in great depths （5-10 km） is a scientific fact. Such deposit occurs around the globe. Thereby, everybody is enabled to generate autonomously clean and renewable energy, ample electricity and heat. The economical exploration and exploitation of this superdeep geothermal heat deposit requires a novel drilling technique, because the currently only deep drilling method （Rotary） is limited to about 5 km, due to the rising costs, depending exponentially on depth. Electro-pulse-boring （EPB） is a valuable option to Rotary drilling. EPB, originally investigated in Russia, is ready to be developed for industrialization. The feasibility of EPB is proven by many boreholes drilled up to 200 m in granite （crystalline）. Estimates show outstanding low costs for drilling by EPB： 100 E/m for a borehole with a large diameter （φ） such as 20 （50 cm）, independent on depth and applicable likewise for sediments and crystalline rocks, such as granite. The current rate of penetration （ROP） of 3 m per hour is planned to be augmented up to 35 m per hour, and again, irrespective whether in sedimentary or crystalline formations. Consequently, a 10 km deep borehole with φ 50 cm will ultimately be drilled within 12 days. EPB will create new markets, such as： （i） EPB shallow drilling for geotechnics, energy piles, measures in order to mitigate natural hazards, etc., （ii） EPB deep drilling （3-5 km） for hydro-geothermics, exploration campaigns etc. and （iii） EPB super-deep drilling （5-10 km） for petro-geothermies, enabling the economic generation of electricity. The autonomous and unlimited supply with cost efficient electricity, besides ample heat, ensures reliably clean and renew- able energy, thus, high supply security. Such development will provide a substantial relief to cope with the global challenge to limit the climate change below 2 ℃. The diminution of fossil fuels, due to the energy transition in order to mitigate the climate change, implies likewise the decrease of air pollution.展开更多
Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circum...Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.展开更多
基金G.Z.acknowledges funding support from NIH(R01CA266981,R01AI168684,R35GM143014,R21NS114455)DoD CDMRP Breast Cancer Breakthrough Award Level II(BC210931/P1)+3 种基金NIH-NCATS KL2 scholarship(KL2TR002648)via VCU C.Kenneth and Dianne Wright Center for Clinical and Translational Research(UL1TR002649)American Cancer Society Research Scholar Grant(RSG-22-055-01-IBCD)METAvivor Early Career Investigator Award,among others.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.T.S.and F.C.acknowledge the National Natural Science Foundation of China(52103199,82102203)Guangdong Basic and Applied Basic Research Foundation(2020A1515110811).
文摘Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.
文摘The inexhaustible heat deposit in great depths （5-10 km） is a scientific fact. Such deposit occurs around the globe. Thereby, everybody is enabled to generate autonomously clean and renewable energy, ample electricity and heat. The economical exploration and exploitation of this superdeep geothermal heat deposit requires a novel drilling technique, because the currently only deep drilling method （Rotary） is limited to about 5 km, due to the rising costs, depending exponentially on depth. Electro-pulse-boring （EPB） is a valuable option to Rotary drilling. EPB, originally investigated in Russia, is ready to be developed for industrialization. The feasibility of EPB is proven by many boreholes drilled up to 200 m in granite （crystalline）. Estimates show outstanding low costs for drilling by EPB： 100 E/m for a borehole with a large diameter （φ） such as 20 （50 cm）, independent on depth and applicable likewise for sediments and crystalline rocks, such as granite. The current rate of penetration （ROP） of 3 m per hour is planned to be augmented up to 35 m per hour, and again, irrespective whether in sedimentary or crystalline formations. Consequently, a 10 km deep borehole with φ 50 cm will ultimately be drilled within 12 days. EPB will create new markets, such as： （i） EPB shallow drilling for geotechnics, energy piles, measures in order to mitigate natural hazards, etc., （ii） EPB deep drilling （3-5 km） for hydro-geothermics, exploration campaigns etc. and （iii） EPB super-deep drilling （5-10 km） for petro-geothermies, enabling the economic generation of electricity. The autonomous and unlimited supply with cost efficient electricity, besides ample heat, ensures reliably clean and renew- able energy, thus, high supply security. Such development will provide a substantial relief to cope with the global challenge to limit the climate change below 2 ℃. The diminution of fossil fuels, due to the energy transition in order to mitigate the climate change, implies likewise the decrease of air pollution.
基金Acknowledgements We thank Dr. M. M. Gottesman at the National Cancer Institute for providing MCF7/MDR cells. We thank Dr. K. R. Williams for manuscript review. This work was supported by the National Institutes of Health （Nos. GM079359 and CA133086） and National Key Scientific Program of China （No. 2011CB911000）, the National Natural Science Foundation of China （NSFC） （Nos. 21325520, J1210040, 20975034 and 21177036）, the Foundation for Innovative Research Groups of NSFC （No. 21221003）, the National Key Natural Science Foundation of China （No. 21135001）, National Instru- mentation Program （No. 2011YQ030124）, the Ministry of Education of China （No. 20100161110011）, and the Hunan Provincial Natural Science Foundation （Nos. 12JJ6012 and 11JJ1002）.
文摘Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.
