Lipid–Polymer Nanoparticles (LiPoNs) Mediated Codelivery of AntimiR-21 and Gadolinium Chelate in Triple Negative Breast Cancer Theranostics

RNA-based interventions are particularly promising for next-generation therapeutic strategies and hold significant potential when integrated with diagnostic modalities. Among noncoding RNAs, microRNAs (miRNAs) regulate gene expression post-transcriptionally and represent compelling targets for cancer therapy. However, their clinical translation remains hindered by instability, off-target effects, and limited delivery efficiency. Here, we report the microfluidic synthesis of hybrid lipid–polymer nanoparticles (LiPoNs) that co-deliver an AntimiR-21 and the magnetic resonance imaging contrast agent gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA). The LiPoNs were obtained using coupled Hydrodynamic Flow Focusing (cHFF), enabling precise control over lipid–polymer self-assembly and surpassing the compositional limitations reported with conventional micromixers. The resulting AntimiR-21–Gd-DTPA–LiPoNs exhibited an average hydrodynamic diameter of 124 nm, narrow polydispersity (PDI < 0.2), and encapsulation efficiency up to 60%. In MDA-MB-231 breast cancer cells, treatment with AntimiR-21–LiPoNs induced suppression of miR-21 and a corresponding decrease in migratory capacity, demonstrating effective functional delivery and gene expression modulation. These findings establish a versatile microfluidic platform for engineering multifunctional lipid–polymer nanostructures whose hybrid architecture combines the biocompatibility and membrane fusion capability of lipids with the structural robustness and controlled release properties of polymers, thereby advancing RNA-based theranostic design for precision oncology and related applications.