The metal catalysts encapsulated in nanomaterials have recently been applied successfully in bioorthogonal chemistry for intracellular generation of bioactive compounds. However, the nanomaterial-involved intracellular catalysis is intrinsically different from that in solution or in extracellular fluid. Except for the reactivity of metal catalyst itself, the supporting material's morphology and biocompatibility are essential factors for building optimal nanocatalysts. Herein, we present a new nanocopper-doped cross-linked lipoic acid nanoparticle (Cu@cLANP) that meets the stringent requirements for the intracellular nanocatalyst. It comes from endogenous lipoic acid and can easily achieve the morphology change by different reduction methods. The optimal rugbylike Cu@cLANPs I did show much better catalytic efficiency for intracellular azide−alkyne cycloaddition than that of the other two spherical nanocatalysts Cu@cLANPs II and III, hinting at the importance of nanoparticle morphology for the intracellular bioorthogonal transformation.

Here, a novel latent naphthalimide bearing water-soluble nanoprobes with catechol-Fe(III) cores (Fe@LNNPs) was designed, synthesized, and evaluated for in vivo fluorescence imaging of intracellular thiols, as various diseases are associated with overexpression of cellular biothiols. The Fe@LNNPs are mainly composed of three components. The inner part constitutes pyrocatechol groups, which can coordinate with Fe(III) to form a cross-linked core for improving the stability in the complex biological environment. The naphthalimide group is linked by disulfide with the core to quench the probe fluorescence. The outer part is designed to be a hydrophilic glycol corona for prolonging blood circulation. Also, a biotin group can be easily introduced into the nanoprobe for actively targeting the HepG2 cells. The fluorescence spectra reveals that the Fe@LNNPs can be reduced explicitly by glutathione to trigger the fluorescence emission. Confocal microscopic imagings and animal experiments manifest that the Fe@LNNPs, especially with biotin groups, have much better fluorescence signal imaging compared to the reported small-molecule probe 1' both in vitro and in vivo (up to 24 h). The Fe@LNNPs thus feature great advantages such as specificity, stability, biocompatibility, and long retention time for thiol-recognition imaging and hold potential applications in clinical cancer diagnosis.

Featuring the dendrimer-like properties, the cross-linked small-molecule micelles (cSMs) have been shown to be a good alternative to dendrimers in many applications. Following this trend, herein the copper(I)-chelated cross-linked cyclen micelles (Cu I @cCMs) were created as a nanocatalyst for azide-alkyne cycloaddition. Both alkynes and azides with diverse structures performed with excellent reactivity in water at the parts-per-million (ppm) catalyst usage. Recycle experiments disclosed that the nanocatalyst had only slight decrease of catalytic efficiency after reusing many times. Importantly, the Cu I @cCMs could easily enter cells and carry out the intracellular catalysis for lighting up and/or killing cancer cells.