The development of electrochemiluminescence (ECL) sensors for the sensitive detection of circulating tumor DNA (ctDNA) associated with non-small cell lung cancer (NSCLC) offers a promising approach for early diagnosis
however, the lack of robust and efficient luminophore remains a key limitation to the analytical performance of ECL sensors. Herein, a ECL biosensor is developed using a novel His@ZIF-8/Fe-TCPP (HZTCP) luminophore for the sensitive detection of NSCLC-related ctDNA. The HZTCP luminophore, synthesized using a histidine imidazole framework (His@ZIF-8) as the precursor and tetra-(4-carboxyphenyl) porphyrin ferric chloride (Fe-TCPP) as the luminescent ligand, integrates the photoelectrochemical activity of porphyrin with the porous structure of the MOF, achieving excellent ECL performance. In addition, polyethyleneimine and gold nanoparticle-functionalized covalent organic frameworks (P-COF-AuNPs) serve as interfacial materials to significantly enhance the effective area and conductivity of the sensing interface, increase the solid-state loading of the capture probe, and improve the biosensor's sensitivity. The ECL biosensor achieves a wide detection range of 1 fM to 100 nM with a limit of detection of 0.35 fM, enabling the differentiation of NSCLC patients from healthy individuals through ctDNA detection. This work provides a straightforward approach for designing efficient ECL luminophores and presents a promising method for the rapid detection of non-small cell lung cancer-related ctDNA.