Peptide-mediated core/satellite/shell multifunctional nanovehicles for precise imaging of cathepsin B activity and dual-enzyme controlled drug release

Intracellular imaging of pathologically relevant proteases can provide essential information for the accurate evaluation of disease stage and progression. However, the risks of degradation by nonspecific enzymes during transportation and poor cellular uptake limit the use of peptide-based molecular probes (PMPs) for in situ protease imaging. To overcome these obstacles, a self-protected nanovehicle with a peptide-mediated core/satellite/shell structure was constructed for precise imaging of the protease cathepsin B (Cat B) in situ and the subsequent Cat B-responsive drug release. The self-protected nanovehicles demonstrated excellent resistance to nonspecific enzymolysis, thereby keeping the embedded PMPs intact until they reach the target organelle. Furthermore, the targeting ability of the outer shell facilitated the internalization of nanovehicles into tumor cells via receptor-guided recognition: the protective shell thereafter degraded in the intracellular microenvironment, and Cat B activity was dynamically monitored as the core/satellite structure disassembled. Meanwhile, the peptide-mediated satellite/shell structures served as three-dimensional gatekeepers to lock doxorubicin inside the nanovehicles, and drug release was spatiotemporally controlled by Cat B activity. This study provides important guiding principles for the rational design of self-protected nanovehicles for accurate diagnosis and therapy. A nanomaterial that glows only in the presence of cancer-related protease enzymes also delivers drugs to these cells. The approach from Jun-Jie Zhu and co-workers from Nanjing University uses peptides, modified with fluorescent components, to enter cells and emit light when triggered by protease cleavage. Such probes often show false signals due to degradation of unrelated enzymes; the Chinese team overcame this problem by using silica ‘nanovehicles’ filled with fluorescent dopants. After tethering peptides to the silica core, they switched fluorescence off using a gold nanocluster layer and coated the probe with a molecular coating that rejects enzymes other than the intended biomolecule. Live cell trials revealed the nanovehicles remained dark until digested by specific proteases, separating gold and silica components. Loading drugs into the hollow silica core also enabled targeted release during cleavage. A self-protected nanovehicle with peptide-mediated core/satellite/shell structure was constructed for precise imaging of protease cathepsin B (Cat B) in situ and subsequent Cat B-responsive drug release. The self-protected nanovehicles have demonstrated excellent resistant ability to nonspecific enzymolysis, thereby keeping the embedded peptide-based molecular probes with core/satellite structure intact until reaching the target organelle.