Split bullets loaded nanoparticles for amplified immunotherapy

• Published in: Journal of controlled release Vol. 347; pp. 199 - 210
• Main Authors: Liu, Chendong, Li, Lian, Lyu, Jiayan, Xiang, Yucheng, Chen, Liqiang, Zhou, Zhou, Huang, Yuan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2022
• Subjects: Dendritic cell; Endoplasmic reticulum; Immunotherapy; Mitochondria; Nanoparticle; Dendritic cell; Mitochondria; Nanoparticle; Endoplasmic reticulum; Immunotherapy
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.05.011

Dendritic cells (DCs) play central role in adaptive antitumor immunity, while their function is often hampered by low immunogenicity of tumor tissues and surrounding hostile microenvironment. Herein, a “split bullets” loaded nanoplatform that can bidirectionally injure mitochondria (MT) and endoplasmic reticulum (ER) of tumor cells is developed. After cellular uptake, the released “split bullets” separately target to different subcellular destinations and exert distinct effects on DCs: (1) MT-targeted “bullet” recruits peripheral DCs into tumor sites, due to its capability to trigger adenosine triphosphate release from tumor cells; (2) ER-targeted “bullet” activates tumor-infiltrating DCs, which is attributed to its ability to evoke calreticulin exposure on tumor cells. These effects collectively improve the tropism and reactivity of DCs to tumor-specific antigen in a two-pronged way. As a result of enhanced function of DCs in antigen capture, treatment of the “split bullets” loaded nanoplatform ignites robust immune response to suppress primary melanoma, and establishes systemic immune memory against post-surgical tumor recurrence. Overall, this nanoplatform offers a generalizable approach to boost DCs and augment immunotherapy. “Split bullets” released from the same nanoparticle separately target mitochondria (MT) and endoplasmic reticulum (ER) of tumor cells. MT-targeted “bullet” triggers “find me” signal to recruit dendritic cells (DCs) into tumor, and ER-targeted “bullet” evokes “eat me” signal to activate these DCs. With the two-pronged boosting, DCs can ignite robust antitumor immune response. [Display omitted] •Split bullets released from one nanoparticle separately target cellular mitochondria (MT) and endoplasmic reticulum (ER).•Directing drugs to MT and ER exhibit different modes-of-action on immunogenic cell death induction.•Bidirectional injuring tumoral MT and ER is a two-pronged strategy to recruit and activate dendritic cells for immunotherapy.