High-connectivity 3D covalent organic frameworks (COFs) have garnered significant attention due to their structural complexity, stability, and potential for functional applications. However, the synthesis of 3D COFs using mixed high-nodal building units remains a substantial challenge. In this work, we introduce two novel 3D COFs, JUC-661 and JUC-662, which are constructed using a combination of D2h-symmetric 8-nodal and D3h-symmetric 6-nodal building blocks. These COFs feature an unprecedented [8+6]-c pdp net with rare mesoporous polyhedral cages (~3.9 nm). Remarkably, JUC-661 and JUC-662 exhibit outstanding separation capabilities, achieving adsorption selectivities of 4.3 and 5.9, respectively, for C2H2/CO2 (1/1, v/v) mixtures. Dynamic breakthrough experiments confirm their excellent separation capability, maintaining this performance even under conditions of 100% humidity. Monte Carlo simulations and DFT calculations indicate that the exceptional adsorption performance is attributed to the well-defined pore cavities of the COFs, with fluorination of the building unit further enhancing C2H2 selectivity through improved electrostatic and host-guest interactions. This study expands the structural diversity of COFs and highlights their potential for low-energy separation processes.