Efficient delivery of magnolol via polymer and hybrid lipid-polymer particles to human macrophages

Inflammation is a complex host response to combat infections and eliminate pathogens. While essential for tissue repair and homeostasis, prolonged inflammation can lead to chronic disorders. Specialized pro-resolving mediators (SPMs) regulate both the onset and resolution of inflammation, and promoting their biosynthesis is central to anti-inflammatory research. In this regard, magnolol, a bioactive neolignane extracted from Magnolia officinalis, exhibits potent anti-inflammatory and pro-resolving properties by modulating 15-lipoxygenase (15-LOX) production, the key enzyme for SPM biosynthesis, in human monocyte-derived macrophages (MDMs). However, its potential therapeutic application is hindered due to its hydrophobic nature and limited bioavailability. To overcome these limitations, hybrid lipid-polymer nanoparticles (HNPs; made of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-polyethylene glycol (PEG) and poly(D,L-lactic-co-glycolic acid) (PLGA)), functionalized with either the peptide arginylglycylaspartic acid (RGD) or mannose (MAN), were formulated encapsulating magnolol to specifically target M2-MDMs as key responders of the innate immune system, and were compared to conventionally used PLGA-based nanoparticle (NP) formulations, with and without functionalities. All particles, with sizes ranging from 300 to 500 nm, exhibited high drug loading capacity (LC, 3.65–4.25 %) and effectively enhanced 15-LOX product formation in human M2-MDMs, which implies a successful delivery of magnolol. Interestingly, subsequent internalization studies revealed that HNPs were taken up more rapidly compared to the polymeric NPs within the first 15 min, independently from the targeting unit on the surface of the HNPs. This trend persisted over 60 min and 3 h, as confirmed by flow cytometry and confocal microscopy. Our findings highlight the potential advantage of HNPs as an efficient drug delivery platform for inflammation-targeting therapies, offering advantages over conventional polymeric NPs.