Primary adipocytes as targetable drug depot to prevent post-surgical cancer recurrence.

Surgery followed by adjuvant chemotherapy or radiation therapy remains the mainstream treatment for breast cancer in the clinic. However, cancer recurrence post surgery is still common. In view of the clinical practice that autologous fat tissue grafting is often used to facilitate breast reconstruction after lumpectomy, here we develop an in vivo targetable adipocyte-based drug depot for the prevention of post-surgical cancer recurrence. We show that primary adipocytes can be metabolically labeled with clickable chemical tags (e.g., azido groups), for subsequent conjugation of dibenzocyclooctyne (DBCO)-bearing cargo via efficient click chemistry. The conjugated cargo can retain well on the adipocyte membrane. By incorporating a cleavable linker between DBCO and cargo, the conjugated cargo can be gradually released from the surface of adipocytes to effect on neighboring cells. In the context of breast cancer surgery, azido-labeled adipocytes grafted to the surgical site can capture circulating DBCO-drugs for improved prevention of 4T1 triple-negative breast cancer (TNBC) recurrence and metastasis. This targetable and refillable adipocyte-based drug depot holds great promise for drug delivery, transplantation, and other applications.

Metabolic tagging of extracellular vesicles and development of enhanced extracellular vesicle based cancer vaccines.

As key mediators of cellular communication, extracellular vesicles (EVs) have been actively explored for diagnostic and therapeutic applications. However, effective methods to functionalize EVs and modulate the interaction between EVs and recipient cells are still lacking. Here we report a facile and universal metabolic tagging technology that can install unique chemical tags (e.g., azido groups) onto EVs. The surface chemical tags enable conjugation of molecules via efficient click chemistry, for the tracking and targeted modulation of EVs. In the context of tumor EV vaccines, we show that the conjugation of toll-like receptor 9 agonists onto EVs enables timely activation of dendritic cells and generation of superior antitumor CD8+ T cell response. These lead to 80% tumor-free survival against E.G7 lymphoma and 33% tumor-free survival against B16F10 melanoma. Our study yields a universal technology to generate chemically tagged EVs from parent cells, modulate EV-cell interactions, and develop potent EV vaccines.