Towards a Switchable Nanoparticle Behavior Using Inverse Electron-Demand Diels-Alder Chemistry and Ectoenzyme-Based Ligand Activation

Nanoparticles (NPs) as drug delivery platforms encounter numerous obstacles on their journey from administration to the target site. Often, diametrically opposing particle properties are desirable to overcome biological and physical barriers. Therefore, stimuli-responsive NPs have been developed to allow for specific particle adaptation. In this work, it was demonstrated that NPs can be rendered switchable with respect to their interaction with a receptor through an external chemical stimulus. A combination of the inverse electron-demand Diels-Alder (iEDDA) reaction for subsequent NP functionalization and ectoenzyme-based ligand activation allowed for specific particle tailoring. Building on this, a two-step process for target cell recognition was developed: First, NPs were functionalized with Angiotensin-I (Ang-I) as inactive ligand using iEDDA chemistry. At the target site, the ligand was enzymatically processed to Angiotensin-ll (Ang-II) by cellular ectoenzymes. Ang-ll binds as active ligand to the angiotensin ll type 1 (AT1) receptor on the target cell surface. This enzymatic activation aims to minimize the biological effect of the ligand prior to particle binding, while the NP target cell specificity is increased by a two-step recognition with enzymatic processing and receptor binding.