Controllable Formation of Ternary Inorganic-Supramolecular-Polymeric Hydrogels by Amidation-Fueled Self-assembly and Enzymatic Post-cross-linking for Ultrasound Theranostic

Bioinspired by nature, macroscopic and transcellular self-assembly fueled by chemical or enzymatic reaction has been widely developed, but the controllable self-assembly of peptides around nanosurface remains challenging. Herein, an in situ amidation-fueled self-assembly of oligopeptides and the following enzymatic cross-linking has been introduced to prepare mesoporous silica nanoparticle (MSN)-based ternary inorganic-supramolecular-polymeric nanogels as the multifunctional theranostic agent for combined ultrasound imaging and imaging-guided high-intensity focused ultrasound (HIFU) therapy. In this approach, supramolecular hybrid nanogels (MSN-GI) were first obtained by in situ self-assembling of peptide gelators (NapFFK, NapFFK-acrylic) due to the surface amidation reaction and therefore decrease of pH value. Subsequently, redox stimuli-responsive supramolecular-polymeric hybrid nanogels (MSN-GII) were further obtained via laccase-mediated radical postpolymerization of vinyl peptide gelators with monomer and disulfide cross-linker. The multifunctional theranostic agent (MSN-GII@PFH&DOX) has been finally constructed by loading the therapeutic and ultrasound-sensitive guest molecules (doxorubicin, perfluorohexane). Both the in vitro and in vivo ultrasound contrast imaging and imaging-guided HIFU ablation therapy indicate that this supramolecular-polymeric hybrid nanogel system can serve as a potential theranostic agent for efficient tumor-responsive drug release, intensified ultrasound contrast imaging, and enhanced imaging-guided HIFU therapy.