The excessive activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) in macrophages has been recognized as a critical factor in the exacerbation of severe inflammatory bowel disease (IBD). Consequently, the modulation of macrophage NLRP3 activity may serve as an effective strategy for mitigating IBD. Our study has indicated that bicalutamide, a clinically administered agent, has the capacity to reduce inflammation by promoting the degradation of NLRP3 in a macrophage-specific manner. However, the therapeutic efficacy of bicalutamide in treating colitis has remained limited. In an effort to enhance the precision of NLRP3 regulation, a nano-bicalutamide system targeting macrophages has been developed, which has shown potential to significantly improve the therapeutic impact on colitis. Mechanistically, it has been found that this system degrades the NLRP3 protein through the autophagy pathway by recruiting the E3 ligase, mitogen-activated protein kinase kinase 1 (MAP3K1), and the autophagy receptor protein optineurin (OPTN). Furthermore, our findings have indicated that the degradation of macrophage NLRP3 inhibits its M1-type polarization, which in turn hinders the colitis process. The system that we have devised has demonstrated potential to address the urgent need for the treatment of colitis, as well as other diseases related to macrophage NLRP3 dysregulation.