Therapeutic Delivery to the Brain via the Lymphatic Vasculature.

Targeted delivery of therapeutics to disease sites has been one of the biggest challenges in medicine, as it determines the treatment efficacy of virtually all chemical and biological drugs. Furthermore, it is particularly difficult to achieve for diseases in the brain because of an additional barrier compared to other organs, the blood-brain barrier (BBB). Here, we report a new mechanism for drug delivery to the brain, nanoparticle-mediated transport through the newly discovered brain lymphatic vasculatures, bypassing the BBB and other issues associated with conventional intravenous (i.v.) administration. Using indocyanine green (ICG)-loaded PLGA nanoparticles as a model, we show that drug uptake in the brain by subcutaneous (s.c.) injection at the neck near a local lymph node is 44-fold higher than the i.v. route, resulting in effective treatment of glioblastoma in mice by photodynamic therapy. These findings will open a new paradigm for the treatment of a variety of diseases in the brain.

BV2 Membrane-Coated PEGylated-Liposomes Delivered hFGF21 to Cortical and Hippocampal Microglia for Alzheimer's Disease Therapy.

Microglia-mediated inflammation is involved in the pathogenesis of Alzheimer's disease (AD), whereas human fibroblast growth factor 21 (hFGF21) has demonstrated the ability to regulate microglia activation in Parkinson's disease, indicating a potential therapeutic role in AD. However, challenges such as aggregation, rapid inactivation, and the blood-brain barrier hinder its effectiveness in treating AD. This study develops targeted delivery of hFGF21 to activated microglia using BV2 cell membrane-coated PEGylated liposomes (hFGF21@BCM-LIP), preserving the bioactivity of hFGF21. In vitro, hFGF21@BCM-LIP specifically targets Aß1-42-induced BV2 cells, with uptake hindered by anti-VCAM-1 antibody, indicating the importance of VCAM-1 and integrin α4/ß1 interaction in targeted delivery to BV2 cells. In vivo, following subcutaneous injection near the lymph nodes of the neck, hFGF21@BCM-LIP diffuses into lymph nodes and distributes along the meningeal lymphatic vasculature and brain parenchyma in amyloid-beta (Aß1-42)-induced mice. Furthermore, the administration of hFGF21@BCM-LIP to activated microglia improves cognitive deficits caused by Aß1-42 and reduces levels of tau, p-Tau, and BACE1. It also decreases interleukin-6  (IL-6) and tumor necrosis factor-α (TNF-α) release while increasing interleukin-10 (IL-10) release both in vivo and in vitro. These results indicate that hFGF21@BCM-LIP can be a promising treatment for AD, by effectively crossing the blood-brain barrier and targeting delivery to brain microglia via the neck-meningeal lymphatic vasculature-brain parenchyma pathways.