Cell Derived Biomimetic Extracellular Vesicles For Enhanced Antitumor Effect By Combinational Therapy

The combination of multiple modalities has shown great potential in cancer treatment with improved therapeutic effects and minimized side effects.It is essential to develop safe and effective drug delivery system to codeliver therapeutic agents with different properties for combinational therapy.With innate biocompatibility and intrinsic biomimetic properties,cell derived extracellular vesicle can be used as an appealing vehicle for drug delivery.Moreover,this kind of membrane vesicles can mimic the function of parent cells and mediate intracellular communication.Here in order to investigate the application of biomimetic drug delivery system for cancer combinatorial therapy,we developed two kinds of dendritic cell-derived extracellular vesicles for immunochemotherapy and photothermal-chemotherapy.Firstly,we found that various types of cell can change the cytoskeleton and shed microvesicles(MVs)with biomimic properties as parent cells in response to stimuli.To take use of the drug package capability of MVs and the potent antigen presentation property of dendritic cells(DCs),DC derived antigenic MVs were constructed by priming DCs with tumor derived MVs and then encapsulating chemotherapeutic drug during MVs shedding.This kind of MVs can promote the uptake by tumor cells and enhance the cytotoxic effect to tumor.Besides,the MVs can directly stimulate immune cells.In the murine melanoma model,the MVs exhibited significant inhibition on both tumor growth and lung metastasis.The possible mechanism of immunochemotherapy was then investigated.The packaged chemotherapeutics in MVs can induce direct cytotoxicity and immunogenic cell death of tumor cells.Moreover,a robust antitumor immunity was induced both in tumor draining lymph node and tumor microenvironment as the increased infiltration and activation of T lymphocytes.This kind of MVs was further explored in a hepatic ascites model with remarkable prolonged overall survival of mice.More importantly,the MVs can extend the survival of 60% mice more than 150 days with ascites free even after re-challenging tumor twice,demonstrating the flexibility and applicapability of this kind of MV mediated immunochemotherapy.Furthermore,we fabricated a kind of doxorubicin encapsulated biomimetic nanovesicles(NVs)by a facile method with near-infrared dye insertion in the membrane for combinatorial photothermal and chemotherapy.With innate biomimetic properties,NVs enhanced the uptake by tumor cells while reduced the phagocytosis of macrophages.Upon laser irradiation,NVs can convert the absorbed fluorescent energy into heat for effective tumor killing.The hyperthermia can further induce membrane ablation of NVs to accelerate the release of chemotherapeutic drug for potent cytotoxicity to tumor cells.The NVs improved the drug accumulation and showed more efficient in vivo photothermal effect with rapid temperature increase in tumor.Moreover,the NVs based combinational photothermal and chemotherapy exhibited significant tumor growth suppression with a high inhibitory rate of 91.6% and negligible systemic toxicity.In summary,we successfully prepared two kinds of cell-derived biomimetic extracellular vesicles for combinational therapy against cancer.With intrinsically high biomimetic properties,the two extracellular vesicles can be efficiently taken up by tumor cells and induce effective cytotoxicity for tumor killing.After injection,the extracellular vesicles can be enriched in tumor site,realize satisfied synergistic antitumor effect and show good systematic safety.Therefore,the cell-derived biomimetic extracellular vesicles can work as a kind of safe and effective drug delivery system.And the vesicles mediated combinational therapies have achieved high therapeutic efficiency in cancer treatment,which would provide theoretical basis and new inspiration for devoloping more advanced multi-modality strategies to fight against tumor.