Despite the enormous therapeutic potential of chemotherapy,due to the lack of effective drug delivery system and poor pharmacokinetics,it often caused non-specific toxicities to normal organs or tissues,which limits its further application in clinics.Moreover,it only benefits small subset of patients and the drug response rate in overall patients is unsatisfactory because of the heterogeneity.Mono-chemotherapy often cannot achieve the desired outcomes,and may lead to the drug resistance.Hence,an urgent need is required to develop a novel drug delivery system to address the aforementioned obstacles.Recently,with the development of nanotechnology and biomedical engineering,bioinspired drug delivery system has been developed due to its preferential biocompatible and tumor targeting.Especially,cell membrane vesicle-based bioinspired drug delivery system,it can integrate the biofunctions of the derived natural membrane and the physicochemical properties of the synthesized nanoparticles.Cell membrane coted nanoparticle has a typical core-shell structure,and the inner cores can be drived from various multifunctional nanoparticles,which can combine serval therapies as multi-modal therapies including chemotherapy,immunotherapy,chemodynamic therapy(CDT),photodynamic therapy(PDT),photothermal therapy(PTT)and sonodynamic therapy(SDT).There are many important functional proteins existing on the membrane such as CD47,which can inhibit the endocytosis by macrophages and thus prolong the circulating time.We can also display some important proteins,peptides or antibody on the cell membrane by genetically engineering,and utilize it to target tumor or stimulate immune response.Above all,the cell membrane coated nanoparticles as novel anti-cancer nanomedicine can largely promote the clinical translation,representing a promising strategy in cancer therapy.Considering the facts,we selectively display TRAIL(tumor necrosis factor apoptosis-inducing ligand)on the HUVECs(human umbilical vein endothelial cells)and derive its vesicles as drug co-delivery carrier by using its tumor targeting,and we also display anti-DEC205 on the Hep 1-6 and drive its vesicles to coat sono-sensitive nanoparticles to realize the combination of chemotherapy,SDT and immunotherapy by using the DCs targeting and tumor homologous targeting.We summarize the two main researches and the highlights as follows:In the first part,we firstly derived TRAIL-HUVEC cell membrane vesicles(TH-V)and coated onto the active tumor-targeting nanocarrier(TH-NP)to co-deliver OXA(Oxaliplatin)and autophagy inhibitor HCQ(hydroxychloroquine),which can inhibit the protective autophagy flux for enhancing chemosensitivity,and simultaneously inhibited cancer distant metastasis.Due to the design,the outer membrane TRAIL-DR4/5(death receptors 4/5)interactions resulted in a tumor targeting drug delivery,leading to the effective tumor biodistribution of OXA and HCQ while sparing on normal cells.The released HCQ could alkalize or damage the lysosome,which blocked the OXA-induced protective autophagy mediated FAs disassembly,and finally inhibited cancer cell invasion and migration.The in vivo antitumor effect on HCCLM3 subcutaneous and high-metastatic orthotopic tumor models showed TH-NPs treatment can significantly inhibit tumor growth.In addition,in the metastatic mouse models,the amount metastatic pulmonary nodules after TH-NPs treatments was largely decreased.Next,we investigated the detailed mechanism,and found the remarkable antitumor effect of TH-NPs was attributed to the targeting design,of which the enhanced tumor distribution of HCQ overcame OXA-triggered protective autophagy.Then,the degradation of tumor metastatic marker proteins FAs including the E-cadherin and paxillin was reversed.Collectively,we rationally designed the biomimetic co-delivery nanoparticle TH-NP to efficiently inhibit protective autophagy flux,and then suppress tumors growth and distant metastasis in vitro and vivo.TH-NPs may represent a promising strategy for HCC therapy in clinics.In the second part,we constructed anti-DEC205-Hep1-6 cell membrane vesicles coated nanoparticles as a novel multi-modals theranostic nanoplatform.It can combine SDT,CDT and immunotherapy,and successfully achieved this program with the constructed sonosensitizer carrier to deliver the immune adjuvant.We synthesized a metal organic framework with sonosensitizer as structural unit,loaded R848 with its porous properties,and reduced Au and Pt atoms on its surface to form a thin AuPt shell.We encapsulated prepared agents through genetically engineered DEC-205 homologous cell membrane,promote the accumulation of nanoparticles in tumors,thereby improving the therapeutic effect.Moreover,anti-DEC025 can target tumor infiltrating DCs(TIDCs),and thus promote DC maturation,antigens endocytosis and MHC-I cross presentation.After the SDT,the released tumor associated antigens can further stimulate DCs and immune response with the help of R848.Briefly,the bioinspired multi-functional integrated platform presents excellent theranostics features:(1)it can directly target TIDCs and promote tumor antigens MHC-I cross presentation;(2)bimodal imaging real-time monitors drug enrichment in vivo to provide guidance for optimal ultrasound processing time;(3)Under ultrasound activation,R-MOF@AuPt can produce ROS to directly kill tumors and generate tumor-associated antigens and the released tumor-associated antigens are then amplified by R848-containing R-MOF@AuPt as an immunoadjuvant,could trigger stronger infiltration of cytotoxic T lymphocytes into distant tumors.Our study combined SDT with immunotherapy to develop potential drugs for the treatment of liver cancer. |