Bone morphogenetic protein 2 (BMP-2) has been reported to facilitate epithelial-to-mesenchymal transition (EMT) and bone metastasis in breast cancer xenograft models. To investigate the role of BMP-2 in the development of breast cancer stem cells (BCSCs), and to further elucidate the mechanisms underlying its influence on breast cancer metastasis, we conducted a comprehensive molecular study using breast cancer cell lines and clinical samples. Our results showed that downregulation of Rb by BMP-2 was associated with ubiquitin-mediated degradation activated by phosphorylation of Rb via the PI3K/AKT signal pathway. In addition, the Smad signaling pathways are implicated in upregulation of CD44 protein expression by BMP-2. It was suggested that cross-talk exists between Rb and CD44 signaling pathways, as recombinant human BMP-2 (rhBMP-2) was found to regulate CD44 expression partly through Rb signals. In clinical tissues, BMP-2 was positively and negatively correlated with CD44 and Rb expression, respectively. Based on the in vitro and in vivo results, we have established an integrated mechanism by which rhBMP-2 induces EMT and stemness of breast cancer cells via the Rb and CD44 signaling pathways, which then contribute to breast cancer metastasis. These findings may be helpful for developing new strategies for the treatment and prognosis of advanced breast cancer.

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Although capsule-like materials as host carriers for enzyme encapsulation have been a hot topic in recent years, creating an ideal microenvironment for enhanced enzymatic performance is still a formidable challenge. Herein, we created a template-free method to in situ encapsulate natural enzymes in hollow covalent organic framework (COF) capsules at room temperature. The COF crystallites migrated from the inner core and self-assembled at the outside walls during the inside-out Ostwald ripening process, retaining the enzymes in the cavity. The adjustable hollow structure of the enzyme@COF capsule allowed the basic vibration of the enzyme to maintain a certain degree of freedom, thus significantly enhancing the enzymatic bioactivity. The hollow enzyme@COF capsule has large mesoporous tunnels allowing the efficient transport. In addition, the enzyme encapsulated in the capsule showed superior activity and ultrahigh stability under various extreme conditions that may lead to enzyme inactivation, such as high temperature, organic solvents, chelates, and the denaturing agent. Finally, the prepared hollow GOx@COF capsule was used for electrochemical sensing of glucose in human serum, and the electrochemical sensor exhibited high selectivity and satisfactory test results. This research not only provides a new way for COFs to encapsulate enzymes but also has potential applications in biocatalysis and biosensing, making artificial organelles possible.

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In recent years, metal–organic frameworks (MOFs) have been extensively studied as candidate enzyme immobilization platforms. However, conventional MOF–enzyme composites usually exhibit low controllability and reusability. In this study, a novel and stable strategy for enzyme immobilization was designed by use of ZIF-8 to encapsulate in situ DNA–enzyme composites on the surface of magnetic particles (MPs). The mechanism of in situ encapsulation was discussed in detail. It was found that immobilized enzymes were involved in the growth of ZIF-8, and the DNA cross-linking agents promoted the growth of ZIF-8 on the surface of MP. The thermal, chemical, and physical stabilities of horseradish peroxidase (HRP) were all significantly enhanced after in situ encapsulation. Most importantly, this strategy was proven to be a general platform that can be used to stabilize various proteins. The in situ encapsulation strategy was expanded to immobilize a cascade of enzymes, and ZIF-8@MPGOx–HRP possessed high selectivity and a wide linear range (25–500 μM) for glucose detection.