  Effective and controlled drug delivery systems with on-demand release and
targeting abilities have received enormous attention for biomedical
applications. Here, we describe a novel enzyme-based cap system for mesoporous
silica nanoparticles (MSNs) that is directly combined with a targeting ligand
via bio-orthogonal click chemistry. The capping system is based on the
pH-responsive binding of an aryl-sulfonamide-functionalized MSN and the enzyme
carbonic anhydrase (CA). An unnatural amino acid (UAA) containing a norbornene
moiety was genetically incorporated into CA. This UAA allowed for the
site-specific bio-orthogonal attachment of even very sensitive targeting
ligands such as folic acid and anandamide. This leads to specific
receptor-mediated cell and stem cell uptake. We demonstrate the successful
delivery and release of the chemotherapeutic agent Actinomycin D to KB cells.
This novel nanocarrier concept provides a promising platform for the
development of precisely controllable and highly modular theranostic systems.
