TRIM21-dependent ultrasmall chiral gold nanoparticles for preventing microglia senescence against Alzheimer’s disease

Tripartite motif 21 (TRIM21) is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination. Here, ultrasmall chiral gold nanoparticles (D- or L-NPs) modified by D- or L-glutathione ligands were fabricated. After conjugated with an NLR family pyrin domain-containing protein 3 (NLRP3) antibody (D-NP-aNLRP3 or L-NP-aNLRP3), D-NP-aNLRP3 showed effective delivery efficiency of the antibody into microglia and prevented Aβ-mediated microglia senescence, and p16^ink4a, a marker of senescence, in the microglia was reduced by 90.3% ± 7.8% while L-NP-aNLRP3 decreased by 48.01% ± 3.1%. Mechanistic investigations revealed that the D-NP-aNLRP3 ((1.5 ± 0.3) × 10⁷ M⁻¹) exhibited sixteen-fold larger binding affinity to transmembrane glycoprotein SLC3A2 than L-type ((9.5 ± 2.7) × 10⁵ M⁻¹), which led to a high efficiency of antibody delivery and TRIM21-dependent NLRP3 degradation. Notably, the blood-brain barrier (BBB)-crossing ability of chiral NP-aNLRP3 as well as NLRP3 degradation was demonstrated in vivo. The APP/PS1 Alzheimer’s disease (AD) model mice experiments exhibited a reduction of 89.7% ± 6.8% for the NLRP3 protein and 84.2 ± 7.5% for p16^ink4a following the intravenous administration of D-NP-aNLRP3 once a week for 60 days. Furthermore, the levels of the AD markers Aβ and phosphorylated-Tau in the brains were reduced by 86.2% ± 8.2% and 81.6% ± 9.1%; these were 2.1-fold and 1.9-fold higher than those treated with L-NP-aNLRP3, respectively. The studies provide a method to rescue AD-like pathologies and prevent senescence.