Iminoboronate Chemistry-Enabled Supramolecular Nanoparticles for Synergistic Combination Therapy

Abstract

Combination therapy has been widely recognized as an effective strategy for the treatment of complex diseases. However, conventional coadministration approaches often suffer from limitations such as pharmacokinetic mismatches, drug–drug interactions, and reduced therapeutic efficacy. Covalent conjugation strategies have emerged as promising alternatives for addressing these challenges, yet their clinical translation is often hindered by laborious synthetic procedures and insufficient dynamic tunability. Herein, we propose a robust and efficient approach for constructing multifunctional supramolecular nanoparticles based on iminoboronate chemistry with high thermodynamic stability and rapid reaction kinetics. This unique chemical reactivity enabled the direct and modular conjugation of amine-containing drugs and natural polyphenols under mild conditions, facilitating the formation of oxidatively responsive nanostructures. Crucially, the rational integration of iminoboronate chemistry allowed relatively precise regulation of drug pharmacokinetics, leading to synchronized biodistribution, temporally coordinated corelease, and enhanced therapeutic synergy. As a proof of concept, nanoparticles (RLZ-OPC NPs) coassembled from riluzole (RLZ) and oligomeric proanthocyanidins (OPC) exhibited potent neuroinflammatory effects in a rat model of intracerebral hemorrhage (ICH), effectively alleviating oxidative stress, suppressing neuroinflammation, and reducing neuronal apoptosis. This work highlights the potential of dynamic iminoboronates as a versatile platform for engineering next-generation nanotherapeutics with programmable pharmacokinetic profiles and synergistic therapeutic effects.