<p>Breast cancer remains one of the most challenging cancers to confront women, and is considered one of the most lethal cancers to this day. Since the cancer was first identified, the search for the most effective treatment continues to evolve. A novel treatment strategy, nanomedicine, has presented a variety of materials that can be adaptively used as drug delivery systems. Myristicin, a natural substance obtained from nutmeg, has been noted for its ability to inhibit cancer cell growth. The present study aimed to explore the concurrent delivery of hyaluronic acid targeted Myristicin-encapsulated PLGA-PEG nanoparticles against breast cancer cells. The PLGA-PEG/M/HA NPs were analysed for their structural, physicochemical, and biological characteristics. The nanoparticles’ morphology and size distribution, examined through dynamic Light scattering and scanning microscopy, indicated that they had a spherical shape and an appropriate size range at 236.6 ± 1.98&#xa0;nm. The PLGA-PEG/M/HA exhibited a significant ζ potential of -25.8 ± 1.23 mV, along with impressive drug loading of 8.2 ± 0.879% and 75 ± 3.12% of encapsulation efficiencies. The PLGA-PEG/M/HA demonstrated effective internalization, cumulative myristicin release (70 ± 3.18%), and dose-dependent cytotoxicity against MCF-7 cells (IC₅₀ at 182.76 ± 1.16&#xa0;µg/ml). Moreover, free myristicin and HA-targeted myristicin-loaded nanoparticles showed no toxic effects on healthy cells (WRL-68). The PLGA-PEG/M/HA significantly triggered cytotoxic effects through the induction of 47.1 ± 2.67% of the early apoptosis and cell cycle arrest at G2/M phase. In contrast, the HA-targeted drug-loaded nanoparticles were notably more effective against cancerous cells compared to the bare myristicin. Our results suggest that the modified PLGA-PEG/M/HA nanoparticles could be a valuable platform for employing phytotherapy with a nano drug delivery system for breast cancer.</p> Graphical Abstract <p></p>