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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, M-CS-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.
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