Hybrid PLGA nanoparticles outperform SLNs in intracellular delivery of an anti-inflammatory lipid mediator to skeletal muscle cells.

Chronic low-grade inflammation (CLGI) contributes to several skeletal muscle disorders as sarcopenia, still lacking disease-specific therapies. Palmitoylethanolamide (PEA) is a natural anti-inflammatory mediator with proven safety, but its high lipophilicity and poor solubility limit bioavailability and muscle delivery. The intrinsic difficulty of actively targeting skeletal muscle cells further supports the need for biomaterial-based strategies to enhance PEA delivery and therapeutic potential. Here, solid lipid nanoparticles (SLNs) and hybrid polymer-lipid PLGA nanoparticles (hyPLGA) are directly compared to identify a nanocarrier optimized for PEA delivery and bioactivity in skeletal muscle tissue. Both carriers exhibited favorable physicochemical profiles and maintained dimensional features after lyophilization, with PEA-SLNs achieving higher encapsulation efficiency. Despite this, PEA-hyPLGA nanoparticles demonstrated superior functional performance in vitro. In C2C12 myoblasts, both formulations were internalized efficiently, yet PEA-hyPLGA nanoparticles exhibited faster uptake kinetic. Notably, PEA-hyPLGA significantly reduced IL-6 and TNF-α transcript levels, enhanced PPAR-α nuclear localization, and mitigated LPS-induced cytotoxicity more effectively than Native PEA or PEA-SLNs. The efficient internalization of PEA-hyPLGA nanoparticles was also observed in human 3D muscle constructs, where the nanoparticles exhibited the ability to penetrate differentiated myofibers. Their behavior was further validated in vivo, where a prolonged retention of PEA-hyPLGA nanoparticles and their ability to reduce inflammatory markers in mouse skeletal muscle, upon intramuscular injection, was observed. Altogether, these findings indicate that hyPLGA nanoparticles represent a convenient nanostructure platform for PEA delivery and anti-inflammatory function in skeletal muscle, supporting their envisaged use as systemic administered targeted therapy toward translational strategies for sarcopenia.