<b>Flash nanoprecipitation for co-delivery of magnetic nanoparticles and small molecules </b><b>in polymeric nanocarriers</b>

Chronic inflammatory diseases may benefit from nanocarrier platforms that co-deliver hydrophobic anti-inflammatory drugs and imaging agents. Here, we report polymeric theranostic nanocarrier dispersions produced by flash nanoprecipitation (FNP) that encapsulate flame-made manganese-doped superparamagnetic iron oxide nanoparticles (SPIONs; Mn0.25Fe2.75O4) together with T‑5224, a model small-molecule inhibitor of the c‑Fos/c‑Jun activator protein‑1 (AP‑1) complex. We first mapped key formulation and process parameters governing dispersion properties, including PLA–PEG molecular weight, total solute concentration, solvent-to-antisolvent ratio, and SPION:polymer mass ratio. These studies identified conditions yielding smaller, narrowly distributed dispersions. Using the optimized formulation, T‑5224/SPION nanocarrier dispersions were purified by magnetic separation and exhibited hydrodynamic diameters <200 nm with low dispersity (PDI < 25%) and long-term colloidal stability in water at room temperature for up to six months. Acidification of these previously stable dispersions (pH 4.5–1) induced rapid destabilization within hours, supporting pH-responsive disassembly behavior relevant to endolysosomal environments. The dispersions provided strong T2 MRI contrast, with a measured relaxivity of r2 = 0.273·(mM−1·ms−1) at 9.4 T, demonstrating retained SPION relaxivity after encapsulation. T‑5224 encapsulation efficiency remained low (≤5%), indicating the need for further process optimization and mass-balance studies. In vitro assays (MTT and crystal violet) showed no detectable cytotoxicity across tested concentrations in Caco‑2 and NIH/3T3 cells. Overall, this work establishes a scalable FNP route to theranostic nanocarrier dispersions and defines key formulation constraints for future improvement of drug loading and functional anti-inflammatory delivery.