Abstract 6895: Efficacy and mechanism of homologous targeting mediated by cancer cell derived membrane nanovesicles for cancer diagnosis and treatment

Abstract Background: Malignant tumor is one of the major diseases threatening human health. Nanosized drug delivery systems (NDDS) have achieved enormous improvements in the diagnosis and treatment of cancer by enhancing therapeutic drug delivery into tumor tissues. More recently, there has been increased interest in utilizing natural materials directly to create biomimetic NDDS. Among the different bioinspired strategies, cellular membrane nanovesicles (MNVs) offer the advantage of being able to fully replicate the diversity of antigens on the surface source cells. Specific proteins such as adhesive proteins and integrins are highly expressed on the surface of cancer cell membrane (CCM), which readily endows homologous tumor cells with strong adhesion and high self-recognition capabilities. However, the mechanism regarding the homotypic affinity of cancer cells remains unclear. Methods and Results: In vivo imaging and quantitative analysis results showed that MNVs from MDA-MB-468 breast tumor cells (M468-MNVs) can actively recognize and “home” to the homologous MDA-MB-468 tumor while to a great extent “bypassing” the coexisting heterologous MDA-MB-231 breast tumor. The secreted chemokine from two kinds of tumor tissues were detected, and the results showed that many kinds of chemokine were high secreted in MDA-MB-468 tumors (e.g. CXCL12, CCL19), not in MDA-MB-231 tumors. The highly-secreted chemokine might lead to the recruitment of membrane nanovesicles with high-level chemokine receptor. To confirm that the candidate proteins are responsible for the homologous-targeting of CC-MNVs, the corresponding antagonists were administrated in vivo to block the interaction between the receptor and ligand. After blocking of CXCR4/CXCL12 or CCR6/CCL19 axis pathway, M468-MNVs showed lower fluorescence signal in tumor tissues. However, M468-MNVs showed the highest fluorescence signal in tumor tissues when there was no chemokine receptor-ligand blocking. Candidate upregulated membrane adhesive proteins was silenced by specific shRNAs. In vivo imaging analysis results showed that the fluorescence of shCXCR4-MNVs decreased significantly in M468 tumors, compared with that of shNC-MNVs. After high efficiency of targeting into tumor tissues, CXCR4-positive M468 MNVs were applied to treat cancer by deliverying therapeutic drug photosensitizer IR780. Upon laser irradiation, the volume of MDA-MB-468 tumor in M468-MNVs treatment group was significantly reduced. In addition, similar to the saline treatment group, mice in M468-MNVs treatment group showed slight body weight gain under laser irradiation, indicating that M468-MNVs and NIR-laser irradiation have very low systemic toxicity. Conclusion: In summary, the CXCR4-positive CC-MNVs platform have great advantages with outstanding antitumor efficiency and safety on tumor models with high-secreted CXCL12. Citation Format: Yanan Tan, Lu Bai, Xinyuan Guan. Efficacy and mechanism of homologous targeting mediated by cancer cell derived membrane nanovesicles for cancer diagnosis and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6895.