Ultrasmall Fe‐curcumin immunomodulators reinvigorate CAR‐T cells to potentiate solid tumor immunotherapy by mitigating cell exhaustion and senescence

Abstract CAR‐T cell immunotherapy has achieved exciting success in hematologic malignancies, but the therapeutic efficacy is relatively limited in solid tumors due to negative cause induced suppressed cell expansion capability, limited infiltration ability as well as serious cell exhaustion and senescence. Herein, we creatively developed ultrasmall Fe–curcumin (Fe–Cur) immunomodulator energized CAR‐T cells to potentiate solid tumor immunotherapy by mitigating CAR‐T cell exhaustion and senescence. The ultrasmall Fe–Cur nanoparticles were synthesized by a facile coordination reaction between curcumin and Fe 3+ with 5 nm uniform size and excellent T1 weight MRI property. In addition, the Fe–Cur nanoparticles possess large positive potential, endowing effective combination with the negative potential of the CAR‐T cell membrane through electrostatic attraction. The Fe‐Cur nanoparticles potently enhance tumor cell killing capacity by alleviating CAR‐T cell senescence through p53 pathway suppression while mitigating T cell exhaustion. Moreover, in vivo studies demonstrate that Fe‐Cur nanoparticle‐enhanced CAR‐T cell therapy synergistically improves solid tumor treatment outcomes, with real‐time MRI guidance monitoring therapeutic responses. More significantly, Fe–Cur nanoparticles demonstrate potent tumor microenvironment‐modulating capacity by alleviating hypoxia conditions, thereby enhancing both CAR‐T cell and endogenous immune cell infiltration while reprogramming tumor‐associated macrophages. The relived tumor microenvironment further activated the innate immunoactivity and stimulated CAR‐T cell viability. The well‐designed Fe–Cur nanoparticle‐ modified CAR‐T cell‐ based immunotherapy strategy not only provides an effective solid tumor treatment strategy but also extends a novel biomaterial‐ conjugated immune cells‐based therapeutic with firm supporting evidence and guidance.