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Brain-tumor-seeking and serpin-inhibiting outer membrane vesicles restore plasmin-mediated attacks against brain
Mengyuan Zhou1, Yuanyuan Lin1, Haiyan Chen2
1Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
Abstract:
Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases.
Insights
New outer membrane vesicles (OMVs) target brain metastases by inhibiting serpins, restoring plasmin, and inactivating L1CAM. This novel therapy effectively delays tumor growth and improves survival in mice with brain metastases.
Area of Science:
- Oncology
- Nanomedicine
- Neuroscience
Background:
- Systemic therapies for brain metastases face challenges due to the blood-brain barrier and intrinsic resistance mechanisms.
- Brain metastatic cells can evade anti-angiogenesis treatments by upregulating serpins, promoting vessel co-option via L1CAM.
- Existing treatments often show limited efficacy against intracranial tumors.
Purpose of the Study:
- To develop a novel drug delivery system targeting brain metastases.
- To overcome blood-brain barrier limitations and brain-specific resistance.
- To investigate the therapeutic potential of targeting the serpin/plasmin/L1CAM axis in brain metastases.
Main Methods:
- Engineered outer membrane vesicles (OMVs) decorated with brain-tumor-homing ligands (targeting GRP94 and vimentin).
- Loaded OMVs with dexamethasone and embelin to inhibit serpins and regulate the tumor microenvironment.
- Administered DE@OMVs systemically to mice with experimentally induced brain metastases.
Main Results:
- DE@OMVs successfully crossed the blood-brain barrier and selectively entered metastatic cancer cells.
- Treatment led to reduced serpin secretion and restored plasmin production within the tumor microenvironment.
- Significant L1CAM inactivation, decreased tumor cell proliferation, and induced apoptosis were observed.
- Delayed intracranial tumor growth and prolonged survival in treated mice.
Conclusions:
- DE@OMVs represent a potent and selective systemic therapy for brain metastases.
- Targeting the serpin/plasminogen activator/plasmin/L1CAM axis is a viable strategy for overcoming treatment resistance.
- This nanomedicine approach shows promise for improving outcomes in patients with brain metastases.
