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  • Cell-Penetrating Nanoparticles Activate the Inflammasome to Enhance Antibody Production by Targeting Microtubule-Associated Protein 1-Light Chain 3 for Degradation.

Cell-Penetrating Nanoparticles Activate the Inflammasome to Enhance Antibody Production by Targeting Microtubule-Associated Protein 1-Light Chain 3 for Degradation.

ACS nano (2020-02-15)
Motao Zhu, Libo Du, Ruifang Zhao, Helen Y Wang, Yuliang Zhao, Guangjun Nie, Rong-Fu Wang
ABSTRACT

Engineered nanoparticles could trigger inflammatory responses and potentiate a desired innate immune response for efficient immunotherapy. Here we report size-dependent activation of innate immune signaling pathways by gold (Au) nanoparticles. The ultrasmall-size (<10 nm) Au nanoparticles preferentially activate the NLRP3 inflammasome for Caspase-1 maturation and interleukin-1β production, while the larger-size Au nanoparticles (>10 nm) trigger the NF-κB signaling pathway. Ultrasmall (4.5 nm) Au nanoparticles (Au4.5) activate the NLRP3 inflammasome through directly penetrating into cell cytoplasm to promote robust ROS production and target autophagy protein-LC3 (microtubule-associated protein 1-light chain 3) for proteasomal degradation in an endocytic/phagocytic-independent manner. LC3-dependent autophagy is required for inhibiting NLRP3 inflammasome activation and plays a critical role in the negative control of inflammasome activation. Au4.5 nanoparticles promote the degradation of LC3, thus relieving the LC3-mediated inhibition of the NLRP3 inflammasome. Finally, we show that Au4.5 nanoparticles could function as vaccine adjuvants to markedly enhance ovalbumin (OVA)-specific antibody production in an NLRP3-dependent pattern. Our findings have provided molecular insights into size-dependent innate immune signaling activation by cell-penetrating nanoparticles and identified LC3 as a potential regulatory target for efficient immunotherapy.

MATERIALS
Product Number
Brand
Product Description

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Amyloid Protein Non-Aβ Component, ≥80% (HPLC)
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Gold(III) chloride hydrate, 99.995% trace metals basis
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Tetraoctylammonium bromide, 98%
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Sodium borohydride, purum p.a., ≥96% (gas-volumetric)
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Gold nanoparticles, 5 nm diameter, biotin terminated, PEG 5000 coated, OD 50, dispersion in H2O
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Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
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Sodium citrate tribasic dihydrate, ACS reagent, ≥99.0%