Macrophage-targeted shikonin-loaded nanogels for modulation of inflammasome activation

abstract

This study reports the formulation and delivery of hyaluronic acid-Zein (HA-Zein) nanogels loaded with Shikonin (SK) to selectively attenuate macrophage inflammasome. The self-assembled nanogels, produced by nanoprecipitation, exhibited high encapsulation efficiency, and were selectively internalized by human THP-1-derived macrophages without eliciting cytotoxic responses. Cell treatment with HA-ZeinSK nanogels before stimulation with LPS and Nigericin significantly suppressed caspase-1 activation and IL-1 beta production, indicating inflammasome inhibition. Importantly, HA-Zein-SK nanogels bioinstructed inflammasome activated macrophages towards an antiinflammatory CD163(high)HLA-DRlow phenotype and led to a marked reduction in the release of pro-inflammatory mediators (TNF-alpha, IL-6 and IP-10). Extracellular metabolic profiling additionally revealed SK-mediated downregulation of cellular glycolytic activity, which was corroborated by a significant decrease of glycolytic genes transcription. All in all, our findings demonstrate the potential of bioactive SK containing, self-assembled nanogels to modulate exacerbated responses in innate immune cells and, prospectively, in human tissues where NRLP3 inflammasome is abnormally activated upon injury or disease. (C) 2022 Elsevier Inc. All rights reserved.

keywords

HYALURONIC-ACID; NANOPARTICLES; GLYCOLYSIS; DELIVERY; THERAPY; M2

subject category

Science & Technology - Other Topics; Research & Experimental Medicine

authors

Cardoso, M; Gaspar, VM; Ferreira, C; Silvestre, R; Duarte, IF; Mano, JF

Groups

G5 - Biomimetic, Biological and Living Materials

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

Rede Nacional de Ressonância Magnética Nuclear (PTNMR)

acknowledgements

UIDB/50011/2020; UIDP/50011/2020; LA/P/0006/2020; NORTE-01-0145-FEDER-000013; PD/BDE/127830/2016; CEECIND/00185/2020; CEECIND/1048/2019; SFRH/BD/139539/2018. AcknowledgmentsThis work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MEC (PIDDAC) . It was also supported by the Northern Portugal Regional Operational Programme (NORTE 2020) , under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) and by FCT (grant SFRH/BD/139539/2018 to MC, contracts PD/BDE/127830/2016 to CF, CEECIND/00185/2020 to RS and CEECIND/1048/2019 to VMG) . The NMR spectrometer is part of the National NMR Network (PTNMR) , partially supported by Infrastructure Project No. 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC) .