The nano drug delivery systems facilitate the enhancement of the transportation, effectiveness, and precision of theranostic agents. The common challenges faced by these nanoparticles are nanotoxicity, heterogeneity in biodistribution, off-targeting, and rapid clearance. To address these challenges, the biogenic biomimetic nano-delivery system is an ideal approach because this system acquires natural properties to navigate complex biology. Mostly used biogenic products are extracellular vesicles (EVs) characterized by their innate properties such as proteins, lipids, and genetic elements, acquired from respective mother cells, which have been widely exploited as diagnostic biomarkers to study their respective cellular status. However, heterogeneity in their size, long-term stability, and lower isolation yield limit their use as colloidal nano drug delivery systems. Herein, we put forth the concept of re-engineering where EVs are re-engineered with synthetic liposomes as stable and targeted nanomedicine. In a typical re-engineering, EVs derived from Natural Killer cells, one of the emerging and highly studied cells that naturally seek tumors, were engineered with synthetic liposomes. Tumor-targeting properties of re-engineered nanomedicine were studied using breast cancer cells and tumor-bearing mice models. EVs were collected from cell supernatant using sequential centrifugation, then filtered and assessed for their physical (size, charge, polydispersity, and stability), biological (protein markers) properties, and tumor targeting efficacy using in vitro and in vivo models. These EVs were nano entities with size ranges from 30 to 170 nm with a zeta potential of -19±5 mV, which were re-engineered with a pre-synthesized 150±5 nm liposome by using mechanical extrusion resulting in the formation of monodispersed hybrid liposomal EVs (HLEVs) with a hydrodynamic diameter of 155±5 nm and zeta potential of -41±1.5 mV. These EVs and HLEVs were found to be rich in protein biomarkers present in NK cells such as CD-63, NKG-2D, NKp-30, and a marker for EVs CD-56, TSG101, and ALIX. In vitro and in vivo experiments indicated that the biomimetic HLEVs system efficiently targets and distributes in the targeted cancer cells. Considering the importance of proteins in target recognition and mother nature acquired from NK cells, we are highly optimistic that the proposed construct holds promise in targeting tumors to minimize off-target effects in cancer therapy.

Santosh Aryal

The University of Texas at Tyler

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