The delivery of N-myc downstream-regulated gene 2(NDRG2)self-amplifying mRNA via modified lipid nanoparticles as a potential treatment for drug-resistant and metastatic cancers

The protein,N-myc downstream-regulated gene 2(NDRG2),a tumor suppressor,is significantly decreased or absent in many types of cancer.There is a significant negative correlation between the levels of NDRG2 and the development and progression of cancer tumor recurrence and tumor invasion,in different cancers.In contrast,the in vitro and in vivo overexpression of the NDRG2 protein decreases the proliferation,growth,adhesion and migration of many types of cancer cells.The in vitro overexpression of NDRG2 increases the efficacy of certain anticancer drugs in specific types of cancer cells.We hypothesize that the delivery of the mRNA of the NDRG2 protein,encapsulated by lipid nanoparticles,could represent a potential treatment of metastatic and drug-resistant cancers.This would be accomplished using a self-amplifying mRNA that encodes the NDRG2 protein and an RNA-dependent-RNA polymerase,obtained from an in vitrotranscribed(IVT)mRNA.The IVT mRNA would be encapsulated in a lipid nanoformulation.The efficacy of the nanoformulation would be determined in cultured cancer cells and if the results are positive,nude mice transplanted with either drug-resistant or metastatic drug-resistant cancer cells,would be treated with the nanoformulation and monitored for efficacy and adverse effects.If the appropriate preclinical studies indicate this formulation is efficacious and safe,it is possible it could be evaluated in clinical trials.

An iron-based metal-organic framework nanoplatform for enhanced ferroptosis and oridonin delivery as a comprehensive antitumor strategy

Ferroptosis is a recently discovered pathway for regulated cell death pathway.However,its efficacy is affected by limited iron content and intracellular ion homeostasis.Here,we designed a metalorganic framework(MOF)-based nanoplatform that incorporates calcium peroxide(CaO2)and oridonin(ORI).This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis,thereby enhancing ferroptosis therapy.Fused cell membranes(FM)were used to modify nanoparticles(ORI@CaO2@Fe-TCPP,NPs)to produce FM@ORI@CaO2@Fe-TCPP(FM@NPs).The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously,working in tandem with Fe3t to induce ferroptosis.Photodynamic therapy(PDT)guided by porphyrin(TCPP)significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species(ROS).This selfamplifying strategy promoted robust ferroptosis,which could work synergistically with FM-mediated immunotherapy.In vivo experiments showed that FM@NPs inhibited 91.57%of melanoma cells within six days,a rate 5.6 times higher than chemotherapy alone.FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity.Thus,this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment.

mRNA medicine:Recent progresses in chemical modification,design,and engineering

Messenger RNA(mRNA)is a type of RNA that carries genetic information from DNA to the ribosome,where it is translated into proteins.mRNA has emerged as a powerful platform for development of new types of medicine,especially after the clinical approval of COVID-19 mRNA vaccines.Chemical modification and nanoparticle delivery have contributed to this success significantly by improving mRNA stability,reducing its immunogenicity,protecting it from enzymatic degradation,and enhancing cellular uptake and endosomal escape.Recently,substantial progresses have been made in new modification chemistries,sequence design,and structural engineering to generate more stable and efficient next-generation mRNAs.These innovations could further facilitate the clinical translation of mRNA therapies and vaccines.Given that numerous review articles have been published on mRNA nanoparticle delivery and biomedical applications over the last few years,we herein focus on overviewing recent advances in mRNA chemical modification,mRNA sequence optimization,and mRNA engineering(e.g.,circular RNA and multitailed mRNA),with the aim of providing new perspectives on the development of more effective and safer mRNA medicines.

Necroptosis-elicited host immunity:GOx-loaded MoS_(2) nanocatalysts for self-amplified chemodynamic immunotherapy

Nanoparticles induced potent antitumor immunotherapy plays a significant role for enhancing conventional therapeutic effectiveness.However,revealing the pathway of how nanoagents themselves trigger the host immunity or how to maximize the immunotherapy efficacy still needs further exploration.Herein,rose-like MoS2 nanoflowers modified with 2-deoxy-D-glucose(2-DG)and glucose oxidase(GOx)(MPGGFs)have been successfully fabricated via a one-pot hydrothermal reaction and following one-by-one surface modification as a multifunctional nanocatalyst for photothermal therapy enhanced self-amplified chemodynamic immunotherapy(PTT-co-CDT).By introducing GOx,the obtained MPGGFs exhibited self-amplified chemodynamic therapeutic efficacy under hypoxia tumor microenvironment(TME)because of the raised intracellular H2O2 level via enzyme-catalysis of oxygen.Furthermore,combined with the intrinsic excellent photothermal conversion efficiency of MoS2 nanoflowers,PTT-co-CDT performances by MPGGFs could effectively induce the necroptosis of tumor cells both in vitro and in vivo.Then the induced necroptosis via PTT-co-CDT by MPGGFs could directly trigger host immunity by activating the antigen-specific T-cells(CD4^(+) and CD8^(+)).Finally,the excellent in vivo safety of MPGGFs makes us believe that the successful construction of rose-like multifunctional nanocatalyst not only has great potentials for self-amplified chemodynamic immunotherapy,but also provides a paradigm for exploring necroptosis triggered host immunity for cancer treatment.

Development of mRNA vaccines and their prophylactic and therapeutic applications

Nucleic acid vaccines have attracted enormous attention for resolving the limitations of conventional vaccines using live attenuated viruses. Because nucleic acid vaccines can be produced rapidly in response to the emergence of new virus strains, they are more appropriate for the control of urgent epidemic and pandemic issues. In particular, messenger RNA （mRNA） vaccines have evolved as a new type of nucleic acid vaccines in accordance with their superior protein expression and a lack of mutagenesis as compared with DNA vaccines. Using mRNA vaccines, large amounts of target proteins can be expressed in immune cells for efficient immunization. For instance, antigen-specific vaccination is a feasible option involving the expression of specific antigens in antigen-presenting cells. Immunological reactions are modulated by expressing several proteins associated with stimulation or maturation of immune cells. In addition, mRNA vaccines can stimulate innate immunity through specific recognition by pattern recognition receptors. On the basis of these remarkable properties, mRNA vaccines have been used for prophylactic and therapeutic applications. This review highlights the role of mRNA vaccines as prophylactic vaccines for prevention of future infections and as therapeutic vaccines for cancer immunotherapy. In addition to the conventional type of mRNA vaccines, RNA replicons （self-amplifying mRNA vaccines） will be described.

X射线自由电子激光发展(邀请论文)(英文)

This paper reviews the development of X-ray free-electron lasers ( XFELs) . With the unprecedented characteristics of flexible wavelength tunability ,high brightness ,ultrashort pulse duration ,and fully transverse coherence ,these accelerator-based X-ray light sources will open newfields in physics ,chemistry , material ,and life sciences . Based on the present status of XFELs in the worldwide context ,the future directions are analyzed .A brief summary of the developments of free-electron lasers (FELs) in China is given .