Tissue defect is one of the significant challenges encountered in clinical practice. Nanomaterials, including nanoparticles, nanofibers, and metal-organic frameworks, have demonstrated an extensive potential in tissue regeneration, offering a promising avenue for future clinical applications. Nonetheless, the intricate landscape of the inflammatory tissue microenvironment has engendered challenges to the efficacy of nanomaterial-based therapies. This quandary has spurred researchers to pivot towards advanced nanotechnological remedies for overcoming these therapeutic constraints. Among these solutions, microenvironment-sensitive nanozymes have emerged as a compelling instrument with the capacity to reshape the tissue microenvironment and enhance the intricate process of tissue regeneration. In this review, we summarize the microenvironmental characteristics of damaged tissues, offer insights into the rationale guiding the design and engineering of microenvironment-sensitive nanozymes, and explore the underlying mechanisms that underpin these nanozymes' responsiveness. This analysis includes their roles in orchestrating cellular signaling, modulating immune responses, and promoting the delicate process of tissue remodeling. Furthermore, we discuss the diverse applications of microenvironment-sensitive nanozymes in tissue regeneration, including bone, soft tissue, and cartilage regeneration. Finally, we shed our sights on envisioning the forthcoming milestones in this field, prospecting a future where microenvironment-sensitive nanozymes contribute significantly to the development of tissue regeneration and improved clinical outcomes.Copyright © 2024 Elsevier Ltd. All rights reserved.