Ultrasound-enhanced precision tumor theranostics using cell membrane-coated and pH-responsive nanoclusters assembled from ultrasmall iron oxide nanoparticles

Abstract Design of novel theranostic nanoplatforms integrating precision dynamic imaging modalities, tumor targeting ligands and therapeutic components with enhanced tumor accumulation still remains to be challenging. Here we report a facile strategy to prepare cell membrane (CM)-coated nanoclusters assembled from ultrasmall iron oxide nanoparticles (USIO NPs) with pH-responsiveness as a nanocarrier to load anti-cancer drug doxorubicin (DOX). Citric-stabilized USIO NPs with a size of 3.2 nm were synthesized, modified to have surface amine groups, and crosslinked to obtain pH-responsive nanoclusters (NCs). Then, the formed USIO NCs were loaded with DOX, and coated with cancer CMs to render them with resistance to macrophage cellular uptake and homologous cancer cell targeting specificity. Within the acidic tumor microenvironment, the pH-responsive USIO NCs/DOX@CM with dominant T2 magnetic resonance (MR) imaging performance can be dissociated to form single USIO NPs with T1 MR imaging ability, and simultaneously rapidly release DOX, thereby enabling dynamic T2/T1-weighted MR imaging and chemotherapy of tumors. Further, through the ultrasound-induced sonoporation effect, the dynamic MR imaging and tumor chemotherapy can be further enhanced. The designed USIO NCs/DOX@CM may be developed as a versatile theranostic platform for ultrasound-enhanced targeted precision theranostics of different cancer types.