Structure transformable nanoparticles for photoacoustic imaging-guided photothermal ablation of tumors via enzyme-induced multistage delivery

Abstract

Nanomedicines (NMs) have emerged as promising agents for cancer treatment because of the enhanced permeability and retention (EPR) effect. Multiple biological barriers prevent NMs from efficiently accumulating at the tumor site and penetrating into the tumor tissue, leading to suboptimal therapeutic efficacy. To address this problem, we grafted tiny CuS nanocrystals (NCs) onto the surface of gelatin nanoparticles (GNPs, ~100 nm) to create transformable nanoparticles, denoted as [email protected], which can successively cross the biological barriers from intravenous injection to deep tumor zones via enzyme-induced multistage delivery. These transformable [email protected] possess an initial diameter of approximately 120 nm and significantly accumulated at the tumor site after intravenous administration. Upon accumulation at the tumor site, the over-expressed hydrolases in the tumor microenvironment trigger rapid dissociation of the scaffold (GNPs) of [email protected] and attendant release of the CuS NCs for deeper penetration into the tumor tissue. The spatiotemporal multistage delivery behavior of [email protected] within tumor tissue could be tracked in vivo by photoacoustic imaging in a real-time manner. Following the systemic administration of [email protected], near infrared laser irradiation was further employed and efficient photothermal ablation of tumors was realized in MDA-MB-231 tumor-bearing mice. Taken together, these results indicated that the as-fabricated transformable [email protected] could undergo enzyme-induced multistage delivery for enhanced accumulation at the tumor site and improved penetration into the inner tumor. Furthermore, the transformable [email protected] facilitated efficient photoacoustic imaging-guided photothermal ablation to inhibit tumor growth.