MicroRNAs (miRNAs) play a pivotal role in regulating the expression of genes involved in tumor development, invasion, and metastasis. In particular, microRNA‐124 (miR‐124) modulates the expression of carnitine palmitoyltransferase 1A (CPT1A) at the post‐transcriptional level, impairing the ability of androgen‐independent prostate cancer (PC3) cells to completely metabolize lipid substrates. However, the clinical translation of miRNAs requires the development of effective and safe delivery systems able to protect nucleic acids from degradation. Herein, biodegradable polyethyleneimine‐functionalized polyhydroxybutyrate nanoparticles (PHB‐PEI NPs) were prepared by aminolysis and used as cationic non‐viral vectors to complex and deliver miR‐124 in PC3 cells. Notably, the PHB‐PEI NPs/miRNA complex effectively protected miR‐124 from RNAse degradation,resulting in a 30% increase in delivery efficiency in PC3 cells compared to a commercial transfection agent (Lipofectamine RNAiMAX). Furthermore, the NPs‐delivered miR‐124 successfully impaired hallmarks of tumorigenicity, such as cell proliferation, motility, and colony formation, through CPT1A modulation. These results demonstrate that the use of PHB‐PEI NPs represents a suitable and convenient strategy to develop novel nanomaterials with excellent biocompatibility and high transfection efficiency for cancer therapy.

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