Aim To investigate how chili-derived exosome-like nanovesicle (CDELN) inhibited ox-LDL uptake and reduced ox-LDL-induced intracellular cholesterol accumulation. Methods CDELN were isolated and purified using tissue crushing, differential centrifugation, ultracentrifugation and sucrose density gradient centrifugation. Ox-LDL was used to stimulate THP-1-derived macrophages for 24 hours to establish a foam cell model in vitro, and the effect of CDELN on macrophage foam and its mechanism were further studied. Confocal laser microscopy was used to detect the uptake of CDELN and DiL-acetylated low density lipoprotein (DiL-ac-LDL) by THP-1 macrophages. Oil red O staining was used to detect intracellular cholesterol content and the positive area of oil red O staining in cells was analyzed to evaluate the effect of intracellular lipid accumulation. RT-qPCR and Western blot were used to detect mRNA and protein levels of scavenger receptor A (SRA) and cluster of differentiation 36 (CD36), lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), ATP-binding cassette transporter A1/G1 (ABCA1/G1). The expression of mitogen-activated protein kinase (MAPK) pathway proteins including p-ERK, p-p38 MAPK and p-c-Jun, were also analyzed. Results CDELN were exosome-like nanovesicles with uniform size and double membrane, rich in protein and nucleic acids, which can be taken up by macrophages. The results of DiL-ac-LDL uptake showed that CDELN could inhibit cholesterol uptake of macrophages. Oil red O staining showed that CDELN could reduce ox-LDL-induced intracellular cholesterol accumulation. RT-qPCR and Western blot showed that CDELN could significantly reduce mRNA levels of matrix metalloprotein-9 (MMP-9), SRA, CD36 and LOX-1 and protein levels of p-ERK, SRA, CD36 and LOX-1 in ox-LDL-induced THP-1-derived macrophages. Treatment with the p-ERK agonist Yoda1 diminished the protective effect of CDELN. Conclusion CDELN can significantly inhibit macrophage foam cell formation, and this effect may be associated with the inhibition of phosphorylation levels of ERK1/2 in the MAPK pathway.