We have shown that the water-based nanoreactor technology presented here offers several advantages for 3D COF synthesis when compared to conventional synthetic methods. Firstly, it enables the solubilization of COF-300 precursors in an aqueous medium, thereby simplifying the synthetic process by avoiding hazardous and toxic solvents. Secondly, it operates under mild conditions, such as room temperature and atmospheric pressure, ensuring energy efficiency and ease of implementation. Moreover, we have also demonstrated that this approach enables precise control over the synthesis and growth of COF-300 nanoparticles, a feature that is typically unachievable using conventional COF-based synthetic methods and that has proven to be key to improve processability. We believe that this achievement will also have an important impact on the application and utilization of 3D COFs with nanoscale dimensions, enabling their seamless integration and application in domains that were previously inaccessible with large crystal structures. Particularly, this breakthrough holds the potential to revolutionize areas such as 3D COFs for nano/microrobotic applications and biomedicine, further emphasizing the significance of our findings.