The 26S proteasome is the primary machinery that degrades ubiquitin (Ub)-conjugated
proteins, including many proteotoxic proteins implicated in neurodegeneraton. It has been
suggested that the elevation of proteasomal activity is tolerable to cells and may be beneficial
to prevent the accumulation of protein aggregates. Here we show that purified proteasomes
can be directly transported into cells through mesoporous silica nanoparticle-mediated
endocytosis. Proteasomes that are loaded onto nanoparticles through non-covalent
interactions between polyhistidine tags and nickel ions fully retain their proteolytic activity.
Cells treated with exogenous proteasomes are more efficient in degrading overexpressed
human tau than endogenous proteasomal substrates, resulting in decreased levels of tau
aggregates. Moreover, exogenous proteasome delivery significantly promotes cell survival
against proteotoxic stress caused by tau and reactive oxygen species. These data demonstrate
that increasing cellular proteasome activity through the direct delivery of purified
proteasomes may be an effective strategy for reducing cellular levels of proteotoxic proteins.