Neuroprotective Bioorthogonal Catalysis in Mitochondria Using Protein‐Integrated Hydrogen‐Bonded Organic Frameworks

Abstract

AbstractMitochondria‐targeted bioorthogonal catalysis holds promise for controlling cell function precisely, yet achieving selective and efficient chemical reactions within organelles is challenging. In this study, we introduce a new strategy using protein‐integrated hydrogen‐bonded organic frameworks (HOFs) to enable synergistic bioorthogonal chemical catalysis and enzymatic catalysis within mitochondria. Utilizing catalytically active tris(4,4′‐dicarboxylicacid‐2,2′‐bipyridyl) ruthenium(II) to self‐assemble with [1,1′‐biphenyl]‐4,4′‐biscarboximidamide, we synthesized nanoscale RuB‐HOFs that exhibit high photocatalytic reduction activity. Notably, RuB‐HOFs efficiently enter cells and preferentially localize to mitochondria, where they facilitate bioorthogonal photoreduction reactions. Moreover, we show that RuB‐HOFs encapsulating catalase can produce hydrogen sulfide (H2S) in mitochondria through photocatalytic reduction of pro‐H2S and degrade hydrogen peroxide through enzymatic catalysis simultaneously, offering a significant neuroprotective effect against oxidative stress. Our findings not only introduce a versatile chemical toolset for mitochondria‐targeted bioorthogonal catalysis for prodrug activation but also pave the way for potential therapeutic applications in treating diseases related to cellular oxidative stress.