Extracellular Vesicles Based Self-grown Gold Nanoparticles For Combinatorial Cancer Therapy

Cell to cell communication is vital to the organic system.Intercellular exchange of bioinformation can help resist on lots of diseases such as cancer.Extracellular vesicles(EVs),which were secreted by a variety of mammalian cells,can serve as a miniature of parent cells and mimic the function of parent cells.EVs were always used as a biomimetic platform for drug delivery and biological communications,as they owned good biocompatibility and can convert exogenous drugs to “endogenous drugs”.Here,we developed two kinds of EVs based self-grown biomimetic gold nanoparticles(AuNPs)for chemo-photothermal therapy and immunophotothermal therapy.Firstly,we generated a popcorn-like gold nanostructure exploiting extracellular vesicles(EVs).EVs can serve as the vehicle for chemotherapeutic drug doxorubicin(DOX).Taking advantages of EVs,gold nanoparticles can be then self-grown surrounding the EVs,assembling into popcorn-like nanostructure.The formulated nanopopcorn,consisting of self-grown gold nanoparticles and EVs encapsulated with DOX,retained the photothermal transduction from gold nanoparticle assemblies and cytotoxicity of DOX.The popcorn-like structure coating outside the EVs can prevent the leakage of drugs.Under external near infrared irradiation,gold nanopopcorn can produce hyperthermia to induce tumor ablation and trigger drug release,achieving combinatorial chemo-photothermal therapy.The nanoplatform demonstrated improved cellular internalization,controlled drug release,enhanced antitumor efficacy with tumor inhibitory rate up to 98.6% and reduced side effects.Our design of popcorn-like nanostructure will contribute a novel modality for facile and green synthesis of complex metal nanostructures exploiting natural properties of EVs for combinational therapy.We then tried to develop intracellularly generated AuNPs exploiting specific intracellular environment.It was found that many kinds of cells can be employed to generate AuNPs.What's more,the intracellularly generated AuNPs can be exocytosed with cell derived vesicles as AuNPs trapped vesicles.We further developed a novel immunological AuNP through intracellular formulation and exocytosis for combination of PTT and immunotherapy.Melanoma B16F10 cells were employed to generate AuNPs firstly and then shed nanoparticle trapped vesicles to extracellular environment with retained tumor antigens(AuNP@B16F10).By further introducing the nanoparticles into dendritic cells(DCs),DC-derived AuNPs(AuNP@DCB16F10)were generated with presented antigens,which can induce hyperthermia and provoke antitumor immune responses.It was found that AuNP@DCB16F10 induced combinational immunophotothermal therapy can promote DC maturation,multiple cytokines secretion and T cell activation.This immunological nanoplatform demonstrated efficient inhibition or even eradication of primary tumor,tumor metastasis as well as tumor relapse,with significantly improved overall survival of mice.The nanoparticles mediated cancer therapy exhibited broad applicability in multiple tumor models,indicating the flexibility of the nanoplatform.In summary,we successfully developed two kinds of EVs based self-grown biomimetic AuNPs and employed them on combinational antitumor therapy.They all preserved the biocompatibility and the biomimetic properties of EVs,which can improve the biocompatibility of AuNPs,reduce side effects and further enhance the combinatorial antitumor effect.Our design of “cell factory” can produce biomimetic drugs aiming to lots of disease which can act as an effective treatment modality for further clinical trials.