Immune Cell Membrane-coated Nanodrug Delivery System For Improving Tumor Immunotherapy

Immunotherapy such as immune checkpoint blockade(ICB)and adoptive cell transfer is a revolutionary advance in the field of cancer therapy by providing clinical benefits in long-term tumor growth control and recurrence prevention.The other immunotherapeutic strategies including anticancer vaccines and cytokine supplementary therapies are also making rapid progress.Despite these achievements,cancer immunotherapy faces several main challenges such as low response rate and incidence of severe immune-related adverse effects due to low tumor drug exposure and poor tumor infiltration of T lymphocytes.Nanosized drug delivery systems(NDDS)have attracted considerable interests more than 20 years in biomedical applications,owing to their abilities for targeted drug delivery,combinational therapy and spatiotemporally controlled drug release,etc.,which make it great potential to address current challenges in cancer immunotherapy.On this basis,we present a new strategy to improve the specificity of epigenetic drugs using an engineered T lymphocyte membrane camouflage strategy.ORY-1001,an inhibitor of lysine-specific histone demethylase 1(LSD1),was encapsulated into a programmed death receptor 1(PD1)-displaying nanovesicles,namely OPEN.The OPEN could bind programmed death receptor ligand 1(PDL1)on cancer cells and realize cell specific delivery of ORY-1001,which induced accumulation of mono-and dimethylated H3K4.Epigenetic agent upregulated the expression of IFNs and downstream interferon-stimulated genes such as main histocompatibility complex I(MHC-I)and PDL1.Upregulated MHC-I improved antigen display,which facilitated cancer cell recognition by T lymphocytes.The increased PDL1 was blocked by subsequent OPEN.Compared to free ORY-1001,OPEN increased intra-tumor drug accumulation and reduced liver drug exposure after intravenous injection,which alleviated side effects of ORY-1001.Intra-tumoral ORY-1001 reshaped tumor immune microenvironment(TIME)by increasing the density of mature dendritic cells,the proliferation of cytotoxic T lymphocytes,and the antigen display of cancer cells.As a result,OPEN significantly inhibited the growth of primary tumors and prolonged survival of animals in several tumor models.Our experimental results demonstrated that the replenished PDL1 enabled further ligation of OPEN,which in turn blocked PDL1,and OPEN could replenish intratumoral IFNs and block their immunosuppressive activities,increase the density of tumor infiltration CTLs by 29-fold.The in vivo experiments also confirmed that OPEN remarkably enhanced antitumor efficacy in multiple tumor models including TNBC,melanoma and colon cancer.Interleukin 15(IL15)has the ability to promote the survival and proliferation of nature killer(NK)cells and cytotoxic T lymphocytes(CTLs)and thus plays a pivotal role in controlling cancer progression.But IL15 supplementary therapy suffers from systemic serum cytokine upregulation and non-specific stimulation of cancer cells.Herein,we report a nanovesicle composed of an IL15/IL15 receptor α complex(IL15c)-presenting membrane and doxorubicin-loaded ferritin(Dox-Fn)-based cores,namely Dox FILN,which can significantly increase the densities and activities of intratumoral CTLs and NK cells.Mechanistically,Dox FILN deshell in the acidic tumor microenvironment to release Dox-Fn and membrane-bound IL15 c.Dox-Fn could target transferrin receptors on cancerous cells and intracellularly release Dox which induces immunogenic cell death.Membrane-bound IL15 c can recognize and activate IL15 receptor β/γc heterodimers,and promote the proliferation and activation of CTLs and NK cells.This IL15-displaying nanovesicle presents a potential platform for immunochemotherapy of cancer.We designed immune cell membrane coated nanoparticles which could induce efficient tumor-specific immunoregulation.First,we designed an epigenetic nanomodulator,and successfully addressed two major hurdles of epigenetic therapy,non-specific accumulation and stimulation of both anti-tumoral and pro-tumoral activities.The unique design of their epigenetic nanomodulator is the utilization of engineered T lymphocyte membrane,which realizes tumor-targeted delivery of epigenetic drugs and immune checkpoint blockade.On this basis,we demonstrated a core-shell structured nanovesicle,Dox FILN,for tumor-targeted delivery of membranebound IL15 c and Dox which simultaneously modulate two or more types of intratumoral cells with cell-specificity.In the tumor,the two components could dissociate and interact specifically with their own target cells via ligand-receptor recognition-mediated pathways.With the development of nano-science,NDDS plays a great role in the field of drug delivery,and induce strong specific,high safe and efficient tumor treatment through various biological or chemical responses which could regulate the pharmacokinetic behavior of each therapeutic agent in vivo.