Carbonic anhydrase IX-targeted nanovesicles potentiated ferroptosis by remodeling the intracellular environment for synergetic cancer therapy.

Ferroptosis is one critical kind of regulated cell death for tumor suppression, yet it still presents challenges of low efficiency due to the intracellular alkaline pH and aberrant redox status. Herein, we reported a carbonic anhydrase IX (CA IX)-targeted nanovesicle (PAHC NV) to potentiate ferroptosis by remodeling the intracellular environment. CA IX inhibitor 4-(2-aminoethyl) benzene sulfonamide (AEBS) was anchored onto nanovesicles loaded with hemoglobin (Hb) and chlorin e6 (Ce6). Upon reaching tumor regions, PAHC could be internalized by cancer cells specifically by means of CA IX targeting and intervention. Afterwards, the binding of AEBS could elicit intracellular acidification and alter redox homeostasis to boost the lipid peroxidation (LPO) level, thus aggravating the ferroptosis process. Meanwhile, Hb served as an iron reservoir that could efficiently evoke ferroptosis and release O2 to ameliorate tumor hypoxia. With the help of self-supplied O2, Ce6 produced a plethora of 1O2 for enhanced photodynamic therapy, which in turn favored LPO accumulation to synergize ferroptosis. This study presents a promising paradigm for designing nanomedicines to heighten ferroptosis-based synergetic therapeutics through remodeling the intracellular environment.

METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5.

N6-methyladenosine (m6A) has emerged as the most prevalent post-transcriptional modification on mRNA that contributes prominently to tumorigenesis. However, the specific function of m6A methyltransferase methyltransferase-like 3 (METTL3) in colorectal cancer (CRC) remains elusive. Herein, we explored the biological function of METTL3 in CRC progression. Clinically, METTL3 was frequently upregulated in CRC tissues, cell lines, and plasma samples and its high expression predicted poor prognosis of CRC patients. Functionally, knockdown of METTL3 significantly repressed CRC cell proliferation and migration in vitro, while its overexpression accelerated CRC tumor formation and metastasis both in vitro and in vivo. Mechanistically, METTL3 epigenetically repressed YPEL5 in an m6A-YTHDF2-dependent manner by targeting the m6A site in the coding sequence region of the YPEL5 transcript. Moreover, overexpression of YPEL5 significantly reduced CCNB1 and PCNA expression. Collectively, we identified the pivotal role of METTL3-catalyzed m6A modification in CRC tumorigenesis, wherein it facilitates CRC tumor growth and metastasis through suppressing YPEL5 expression in an m6A-YTHDF2-dependent manner, suggesting a promising strategy for the diagnosis and therapy of CRC.