Hybrid nanoparticles (HNPs) were designed by combining a PLGA core with a lipid shell that incorporated PEG–Lipid conjugates with various functionalities (-RGD, -cRGD, -NH₂, and -COOH) to create targeted drug delivery systems. Loaded with a neutral lipid orange dye, the HNPs were extensively characterized using various techniques and investigated for their uptake in human monocyte-derived macrophages (MDMs) using FC and CLSM. Moreover, the best-performing HNPs (i.e., HNP-COOH and HNP-RGD as well as HNP-RGD/COOH mixed) were loaded with the anti-inflammatory drug BRP-201 and prepared in two size ranges (d_H ~140 nm and d_H ~250 nm). The HNPs were examined further for their stability, degradation, MDM uptake, and drug delivery efficiency by studying the inhibition of 5-lipoxygenase (5-LOX) product formation, whereby HNP-COOH and HNP-RGD both exhibited superior uptake, and the HNP-COOH/RGD (2:1) displayed the highest inhibition.

Inflammation resolution is governed by specialized pro-resolving mediators (SPM), mainly formed from omega-3 polyunsaturated fatty acids (n-3 PUFA) by lipoxygenases (LOX), which terminate inflammatory processes and facilitate healing and tissue repair. Promoting endogenous SPM formation, besides therapeutic SPM application, is an innovative concept for intervention in inflammatory diseases, achievable by allosteric 15-LOX activation. Here, targeted screening of the 29 most frequently applied anti-inflammatory natural products using lipid mediator metabololipidomics uncovered the acylphloroglucinols hyperforin, arzanol, garcinol, Myrtucommulone A and the lignan magnolol as potent 15-LOX activators to elicit robust SPM production in resting human M2-like macrophages. Simultaneous n-3 PUFA supplementation synergistically enhanced SPM formation in these M2-like macrophages, most strikingly with magnolol. Comprehensive targeted metabololipidomics in activated human polymorphonuclear leukocytes, monocytes, and M1-/M2-like macrophages revealed shifts from pro-inflammatory cyclooxygenase (COX) and 5-LOX products to pro-resolving 15-LOX products by magnolol and acylphloroglucinols. Finally, using zymosan-induced peritonitis in mice, application of a magnolol/n-3 PUFA combination confirmed synergistic SPM elevation in vivo. Together, we established an approach based on synergism of natural allosteric 15-LOX activators and supplemented n-3 PUFA to accomplish SPM-based resolution pharmacology.

The nitrile group is a versatile pharmacophore that also functions as an intrinsic, bioorthogonal Raman tag in the silent wavenumber region. This dual role allows visualization of the storage sites and sites of action of the FLAP antagonist BRP-685 within differently polarized macrophages.

Polymeric nanoparticles from PLGA, polyesteramides, and acetalated dextran enabled efficient delivery of anti-inflammatory drugs, highlighting the importance of polymer–drug matching for optimal formulation performance.

The potential of liquid chromatography in deciphering salient features of polymeric materials is demonstrated, particularly in the case where more common polymer analysis techniques show their limitations.

Reactive oxygen species (ROS) are important markers for understanding the cellular condition in the context of diseases and inflammatory reactions to nanoparticle uptake. Their precise localization in the cellular context by high resolution microscopy, such as Transmission Electron Microscopy, is an essential tool to visualize ultrastructural alterations and the formation of ROS. However, till now, only limited staining strategies for the TEM investigation of ROS are applied to identify them into the cellular context which are moreover associate to inherent problems of the staining procedure, such as high toxicity and unspecific precipitation in certain cultivation media. Here we report the development of a novel sensor particle system, which allows intracellular detection of ROS. These sensor particles link cerium chloride to the surface of a poly(2-vinylpyridine) particle which greatly decreased the cytotoxicity of cerium chloride to polymorphonuclear leukocytes and expands the choice of possible cultivation media This significantly improves the literature known staining protocols for the detection of ROS by transmission electron microscopy. The formation of ROS is indicated by the formation of a characteristic needle-like precipitate on the nanoparticles’ surface.