Microfluidic synthesis of intelligent nanoclusters of ultrasmall iron oxide nanoparticles with improved tumor microenvironment regulation for dynamic MR imaging-guided tumor photothermo-chemo-chemodynamic therapy

The development of intelligent stimuli-responsive nanomedicines by integrating tumor microenvironment (TME)-responsive imaging and drug delivery characteristics remains to be essential for precision medicine. Here, we report a microfluidic synthesis approach to process preformed nanoclusters (NCs) assembled from cystamine-crosslinked ultrasmall iron oxide (Fe3O4) nanoparticles to be coated with polydopamine (PDA), loaded with the cisplatin and further camouflaged with cancer cell membranes (CCMs). The created multifunctional NCs (for short, FDPC NCs) with a size of 35.4 nm display good colloidal stability, and possess excellent abilities in tumor microenvironment modulation for intracellular reactive oxygen species production and glutathione (GSH) depletion, in photothermal conversion efficiency, and in anticancer activity, all surpassing the counterpart materials synthesized through traditional wet-chemical method. Due to the CCM camouflage to render the FDPC NCs with homologous tumor targeting, GSH-triggered dissociation of the NCs to form single Fe3O4 nanoparticles, and the GSH- and pH-responsive release of cisplatin and Fe, the developed FDPC NCs can achieve dynamic T2/T1-switchable magnetic resonance imaging and tri-mode photothermo-chemo-chemodynamic therapy of tumors under near infrared laser irradiation. Such developed high-quality FDPC NCs through the microfluidic synthesis may be used for multi-mode precision theranostics of other tumor types and have a great clinical translation potential.