Biosynthesized nanoparticles of Tibetan medicine mercuric sulfide preparation to promote endocytosis and realize drug crossing through blood brain barrier

β-HgS as the main component of Tibetan medicine Zuotai (ZT) is widely used in the treatment of central nervous system diseases. Although the synergism of HgS has been clinically verified for more than 2000 years, its synergetic mechanism is still an unsolved mystery and a huge challenge. Notably, we clearly and intuitively demonstrate that Zuotai or β-HgS is auto-synthesized by organisms into spherical HgS nanoparticles with protein corona, with an overall particle size of 30-195 nm and a core of HgS NPs of 5-7 nm. Further research showed that HgS NPs facilitated the transport of Oxiracetam (ORT), Memantine Hydrochloride (MH) and Entinostat (MS-275) across the blood-brain barrier (BBB), especially the brain accumulation of MS-275 increased by more than three times. Meanwhile, HgS NPs enhanced the effect of MS-275 on spatial learning and memory ability of APP/PS1 mice. Further studies confirmed that HgS NPs increased the permeability of the blood-brain barrier (BBB) by regulating endocytosis (Upregulation of caveolin, clathrin, and dynamin, downregulation P-gp) thereby facilitate the transport of drugs across BBB with more than threefold higher brain accumulation and long-lasting efficiency enhancement (4 days). Our findings reveal that these in vivo-generated HgS NPs provide an efficient, convenient, and biocompatible drug delivery platform for crossing the BBB. Importantly, our findings offer new hopes and ideas for in-depth research on highly valuable and mysterious metal preparations in classic Chinese and Tibetan medicine.