Highlights <p>Large bone defects pose serious clinical problems and rapidly increase morbidity.</p> <p>Cellulose-based scaffolds loaded with cells and bioactive mediators have great potential for bone regeneration and tissue repair.</p> <p>Implanted scaffolds can provide long-term mechanical support and may be beneficial for bone protection by incorporating more inductive miRNAs.</p> Abstract <p>Large bone defects, usually caused by infection, trauma, and/or tumor, pose serious clinical problems and rapidly increase morbidity. To promote the regeneration of damaged bone, tissue engineering has been announced as a promising alternative to conventional treatment methods, including surgery with autograft and allograft implants. Bioengineered composite scaffolds consisting of multifunctional biomaterials mixed with cells and bioactive therapeutic mediators have great potential for bone regeneration and repair. Cellulose-based scaffolds have properties such as fibrous aspect, improved surface reactivity, excellent biocompatibility, high crystallinity, biodegradability, remarkable mechanical properties, and non-toxicity. Cellulose and its derivatives have been used in local drug delivery systems and antibiotics in bone tissue engineering. Compared to drugs, microRNAs are an ideal option to enhance bone regeneration through cellulose scaffolds because they regulate multiple bone-building genes simultaneously. This review highlights cellulose-based composite scaffolds for the delivery of microRNAs effective in bone regeneration.</p> Lay Summary <p>This work is an example of cellulose and its derivatives with tunable elasticity that have been used in local drug delivery systems and antibiotics in bone tissue engineering, which can potentially be extended to a variety of functionalized scaffold designs and tailored biomedical applications. The incorporation of miRNA into the cellulose-based composite allows the simultaneous regulation of multiple bone-building genes.</p> Graphical Abstract