Per-and polyfluoroalkyl substances (PFAS), persistent pollutants found in water sources worldwide, pose significant challenges to conventional remediation methods. This study presents a one-pot, high atomeconomy synthesis of porphyrin-based cationic nanocages (oNCs) as a selective, rapid and efficient solution for PFAS removal, addressing critical gaps in current water treatment technologies. Using liquid chromatography− tandem mass spectrometry (LC-MS/MS), the nanocages�[oNC]8PF 6 , [Co 2+ -oNC]8PF 6 , and [Co 3+ (N�O)-oNC]8PF 6 �were evaluated for their ability to sorb a mixture of 38 PFAS, including emerging contaminants like GenX, from various water matrices at a concentration of 50 ng/mL. The nanocages achieved exceptional PFAS removal efficiencies, with optimal results obtained when [oNC]8PF 6 and [Co 2+ -oNC]8PF 6 were combined in a 1:4 ratio. This mixture created a synergistic effect, enabling the sorption of both short-and long-chain PFAS, achieving average removal efficiencies of 90% in Nanopure and groundwater, and 80% in influent sewage. The nanocage mixture consistently outperformed activated carbon, particularly in complex matrices such as influent sewage, where activated carbon presented lower efficiency, especially for perfluoroalkane sulfonamido substances. The nanocages reached sorption equilibrium within 15 min and maintained performance across multiple methanolic regeneration cycles, highlighting their operational durability. NMR spectroscopy and computational studies revealed that PFAS sorption occurs via hydrophobic and electrostatic interactions, as well as partial intercalation, with selectivity for PFAS molecules bearing sulfonate and sulfonamide head groups and carbon chain lengths of five or more. Early stage eco-toxicological assessments confirmed the environmental safety of these nanocages, showing no adverse effects below a concentration of 0.005 μM. By combining rapid PFAS removal with modular, scalable and sustainable material synthesis, this study sets a new direction for developing precise, environmentally responsible PFAS water treatment solutions.