Polydopamine-coated hollow mesoporous silica nanoparticles loaded with lupeol regulates immune microenvironment in gastric cancer mice by down-regulating IL-10 through regulating NF-?b signaling

Background: Modulating the immune microenvironment is a promising strategy against gastric cancer. Objectives: This study explored the mechanism of polydopamine-coated hollow mesoporous silica nanoparticles loaded with lupeol (Lupeol-PDA-HMSNs) in regulating the immune microenvironment via the NF-?B/IL-10 axis. Methods: Lupeol-PDA-HMSNs were synthesized and characterized. A gastric cancer mouse model was established and mice were randomly assigned to control, free Lupeol, PDA-HMSNs, or Lupeol-PDA-HMSNs groups. Tumor growth was monitored. Immune cell profiles and serum cytokines were assessed by ELISA and flow cytometry. Apoptosis-related proteins and NF-?B pathway markers were evaluated by RT-qPCR and Western blot. NF-?B p65 binding to the IL-10 promoter was examined by ChIP-qPCR. Results: Lupeol-PDA-HMSNs were successfully synthesized, exhibiting a uniform particle size of 24.85 ± 0.14 nm and a zeta potential of -21.8 mV. Compared to the NC group, Lupeol-PDA-HMSNs significantly inhibited tumor growth, showing superior efficacy to both free lupeol and the blank carrier (P<0.05). The treatment markedly reduced the proportion of Tregs, while enhancing the populations of CD3+CD4+ T cells and NK cells, as well as the CD4+/CD8+ ratio. Additionally, it up-regulated the expression of pro-apoptotic proteins Bax and Caspase-3, down-regulated the anti-apoptotic protein Bcl-2 and consequently promoted apoptosis. Furthermore, Lupeol-PDA-HMSNs suppressed the activity of the NF-?B pathway, leading to reduced expression of downstream inflammatory cytokines IL-6, IL-10 and TNF-?. ChIP-qPCR analysis confirmed that NF-?B p65 directly binds to the IL-10 promoter region (-1648 to -1638) and this binding was significantly attenuated by Lupeol-PDA-HMSNs treatment (P<0.01). Conclusion: Lupeol-PDA-HMSNs exert potent anti-tumor effects by promoting apoptosis and modulating the immune microenvironment through inhibition of the NF-?B/IL-10 pathway, highlighting their potential as a nanotherapeutic strategy for gastric cancer.