Yao Tong, Yong Cai, Yanting Wu, Wenkun Zhuo, Jinfeng Liao
The regeneration of complex tissues demands advanced scaffolds that offer biomimetic support and tissue-specific bioactive guidance. However, the materials in clinic face big challenges with immune rejection, limited donors, and unsatisfactory inductive activity. Fortunately, cellulose-based scaffolds have risen as a leading sustainable platform, considering their natural abundance, inherent biocompatibility, and highly tunable properties. This review comprehensively presented their evolution from rational design to potential clinical application. The primary cellulose sources and key detailed engineering strategies, including chemical modification, composite formulation, and bioactive functionalization, were arranged logically. The modification of cellulose can tune the physical, chemical, and biological behavior of scaffolds, along with advanced three-dimensional printing fabrication techniques. These material advances have enabled targeted functional outcomes in preclinical models, demonstrating promise for specific applications such as wound healing and bone repair. However, their broad clinical translation is contingent upon resolving persistent challenges, including controlled biodegradation and immune compatibility, which we critically assess alongside emerging frontiers such as smart responsive systems. By bridging material innovation with clinical needs, this review may provide an integrated perspective to guide future cellulose-based scaffold design for tissue regeneration.