Self-oriented central-tumor delivery of legumain-cleavable vehicles governed by circulating monocyte/macrophage for precise tumor enrichment and immune activation

Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.

Tumor and dendritic cell dual-targeting nanocarriers maximize the therapeutic potential of IDO1 inhibitor in vivo

Researches on indoleamine-2,3-dioxygenase-1(IDO1),a neoplastic pathogenesis-related protein,have provided a new angle of view to regulate malignancy-related immunosuppression.However,the therapeutic efficacy of IDO1 inhibitors is subject to key limitations as both cancer and dendritic cells tend to be trapped in the IDO1-mediated immune dysfunction,which poses challenges to the inhibitory potency of drug regimens in multiple targets.Here,we report on the fabrication technique of a biomimetic nanocarrier that is endowed with the whole array of cancer cell membrane proteins for encapsulating the most used IDO1 probe indoximod(IND).By fully utilizing the homologous adhesion proteins and antigenic motifs on cytomembrane,these nanoparticulate particles are capable of infiltrating tumors and actively accumulating in cancer and dendritic cells,as well as hitching a ride on dendritic cells to tumor-draining lymph nodes.Ultimately,by increasing the distribution of drugs in both tumor cells and dendritic cells in tumor-draining lymph nodes,these formulations greatly enhance the efficacy of IND without the aid of chemotherapeutic drugs,achieving substantial control of tumor growth.Overall,this leverage of bionanotechnology maximizes the therapeutic potential of IND and can provide a theoretical reference for the clinical application of IDO1 inhibitors.