As the foremost cause of cancer‐related death, metastasis consists of three steps: invasion, circulation, and colonization. Only targeting one single phase of the metastasis cascade may be insufficient since there are many alternative routes for tumor cells to disseminate. Here, to target the whole cascade of metastasis, hybrid erythrocyte and tumor cell membrane‐coated nanoparticle (Hyb‐NP) is designed with dual functions of increasing circulation time and recognizing primary, circulating, and colonized tumors. After loading with monensin, a recently reported metastasis inhibitor, the delivery system profoundly reduces spontaneous metastasis in an orthotopic breast cancer model. Underlying mechanism studies reveal that Hyb‐NP can deliver monensin to its action site in the Golgi apparatus, and in return, monensin can block the exocytosis of Hyb‐NP from the Golgi apparatus, forming a reservoir‐like subcellular structure. Notably, the Golgi apparatus reservoir displays three vital functions for suppressing metastasis initialization, including enhanced subcellular drug retention, metastasis‐related cytokine release inhibition, and directional migration inhibition. Collectively, based on metastasis cascade targeting at the tissue level, further formation of the Golgi apparatus drug reservoir at the subcellular level provides a potential therapeutic strategy for cancer metastasis suppression.
Cancer Metastasis Suppression
In article number 2204747, Yuan Huang and co‐workers develop a strategy that enhances the targetability and retention of nano‐drug in Golgi apparatus (GA) for cancer metastasis suppression. Hybrid cell membrane‐coated nanoparticles cascade to delivering cargo into GA, and in return, loaded‐Monensin, an exocytosis inhibitor, blocks nano‐drug exocytosis like steel net. With GA retention of nano‐drug and GA dysfunction, this strategy suppresses metastasis initialization via multiple GA‐related pathways.
Mitochondria-targeting damage has become a popular therapeutic
option for tumor metastasis; however, its efficacy is limited by the
adaptive rescue capacity of nuclei. There is an urgent need for a
dual mitochondrial and nuclear targeting strategy that can also increase
the antitumor capacity of macrophages. In this study, XPO1 inhibitor
KPT-330 nanoparticles were combined with mitochondria-targeting lonidamine
(TPP-LND) nanoparticles. The combination of nanoparticles with a 1:4
ratio of KPT and TL demonstrated the best synergistic effect in restraining
the proliferation and metastasis of 4T1 breast cancer cells. Investigating
the mechanisms both in vitro and in vivo, it was found that KPT nanoparticles not only directly impede tumor
growth and metastasis by controlling the expression of associated
proteins but also indirectly facilitate mitochondrial damage. The
two nanoparticles synergistically decreased the expression of cytoprotective
factors, such as Mcl-1 and Survivin, causing mitochondrial dysfunction
and thus inducing apoptosis. Additionally, it downregulated metastasis-related
proteins like HIF-1α, vascular endothelial growth factor (VEGF),
and matrix metalloproteinase 2 (MMP-2) and reduced endothelial-to-mesenchymal
transition. Significantly, their combination increased the ratio of
M1 tumor-associated macrophages (TAMs)/M2 TAMs both in vitro and in vivo and increased the phagocytosis of tumor
cells by macrophages, thus suppressing tumor growth and metastasis.
In summary, this research revealed that nuclear export inhibition
can synergistically enhance the prevention of mitochondrial damage
to tumor cells, heightening the antitumor properties of TAMs, thereby
providing a viable and safe therapeutic approach for the treatment
of tumor metastasis.
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