Tailored Reconstituted Lipoprotein for Site-Specific and Mitochondria-Targeted Cyclosporine A Delivery to Treat Traumatic Brain Injury

The secondary damage in traumatic brain injury (TBI) can lead to lifelong disabilities, bringing enormous economic and psychological burden to patients and their families. Mitochondria, as the core mediator of the secondary injury cascade reaction in TBI, is an important target to prevent the spread of cell death and dysfunction. Thus, therapeutics that can accumulate at the damaged sites and subsequently rescue the functions of mitochondria would largely improve the outcome of TBI. Cyclosporine A (CsA), which can maintain the integrity of mitochondrial function, is among the most promising neuroprotective therapeutics for TBI treatment. However, the clinical application of CsA in TBI is largely hindered because of its poor access to the targets. Here, to realize targeted intracellular CsA delivery, we designed a lipoprotein biomimetic nanocarrier by incorporating CsA in the core and decorating a matrix metalloproteinase-9 activatable cell-penetrating peptide onto the surface of the lipoprotein-mimic nanocarrier. This CsA-loaded tailored reconstituted lipoprotein efficiently accumulated at the damaged brain sites, entered the target cells, bound to the membrane of mitochondria, more efficiently reduced neuronal damage, alleviated neuroinflammation, and rescued memory deficits at the dose 1/16 of free CsA in a controlled cortical impact injury mice model. The findings provide strong evidence that the secondary damages in TBI can be well controlled through targeted CsA delivery and highlight the potential of a lipoprotein biomimetic nanocarrier as a flexible nanoplatform for the management of TBI.