Scalable fabrication of metal-phenolic nanoparticles by coordination-driven flash nanocomplexation for cancer theranostics.

Although various nanomaterials have been developed for cancer theranostics, there remains a key challenge for effective integration of therapeutic drugs and diagnostic agents into a single multicomponent nanoparticle via a simple and scalable approach. Moreover, the bottlenecks of nanoformulation in composition controllability, colloidal stability, drug loading capability and batch-to-batch repeatability currently still hinder the clinical translation of nanomedicine. Herein, we report a coordination-driven flash nanocomplexation (cFNC) process to achieve scalable fabrication of doxorubicin-based metal-phenolic nanoparticles (DITH) with a hyaluronic acid surface layer through efficient control of coordination reaction kinetics in a rapid turbulent mixing. The optimized DITH exhibited a small hydrodynamic diameter (84 nm), narrow size distribution, high drug loading capacity (26.6%), high reproducibility and pH-triggered drug release behaviors. The studies indicated that DITH significantly increased cellular endocytosis mediated by CD44+ receptor targeting and accelerated intracellular drug release owing to the sensitivity of DITH to environmental pH stimuli. Furthermore, guided by T1-weighted magnetic resonance (MR) imaging function endowed by ferric ions, DITH exhibited prolonged blood circulation, enhanced tumor accumulation, improved therapeutic performance and decreased toxic side effects after intravenous injection in a MCF-7 tumor-bearing mice model. These results confirmed that the developed DITH is a promising vehicle for cancer theranostic applications, and our work provided a new strategy to promote the development of translational nanomedicine.