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Abstract Lipid metabolism is essential for stemness maintenance, self‐renewal, and differentiation of stem cells, however, the regulatory function of cholesterol metabolism in erythroid differentiation is poorly studied. In the present study, a critical role for cholesterol homeostasis in terminal erythropoiesis is uncovered. The master transcriptional factor GATA1 binds to Sterol‐regulatory element binding protein 2 (SREBP2) to downregulate cholesterol biosynthesis, leading to a gradual reduction in intracellular cholesterol levels. It is further shown that reduced cholesterol functions to block erythroid proliferation via the cholesterol/mTORC1/ribosome biogenesis axis, which coordinates cell cycle exit in the late stages of erythroid differentiation. The interaction of GATA1 and SREBP2 also provides a feedback loop for regulating globin expression through the transcriptional control of NFE2 by SREBP2. Importantly, it is shown that disrupting intracellular cholesterol hemostasis resulted in defect of terminal erythroid differentiation in vivo. These findings demonstrate that fine‐tuning of cholesterol homeostasis emerges as a key mechanism for regulating erythropoiesis.

Abstract Growing experience with engineered chimeric antigen receptor (CAR)‐T cells has revealed some of the challenges associated with developing patient‐specific therapy. The promising clinical results obtained with CAR‐T therapy nevertheless demonstrate the urgency of advancements to promote and expand its uses. There is indeed a need to devise novel methods to generate potent CARs, and to confer them and track their anti‐tumor efficacy in CAR‐T therapy. A potentially effective approach to improve the efficacy of CAR‐T cell therapy would be to exploit the benefits of nanotechnology. This report highlights the current limitations of CAR‐T immunotherapy and pinpoints potential opportunities and tremendous advantages of using nanotechnology to 1) introduce CAR transgene cassettes into primary T cells, 2) stimulate T cell expansion and persistence, 3) improve T cell trafficking, 4) stimulate the intrinsic T cell activity, 5) reprogram the immunosuppressive cellular and vascular microenvironments, and 6) monitor the therapeutic efficacy of CAR‐T cell therapy. Therefore, genetic and functional modifications promoted by nanotechnology enable the generation of robust CAR‐T cell therapy and offer precision treatments against cancer.