Ultrasensitive and accurate monitoring of ultralow-level biomarkers is imperiously needed in clinical diagnosis. So far, exploring high-performance photocathodes and developing new sensing strategies have remained central challenges in photoelectrochemical bioassays. Herein, a two-dimensional (2D) pyrene covalent organic framework (COF, PAF-130) is exemplified for the first time as a high-performance photocathode for precise immunosensing of α-synuclein (α-Syn) by integrating a DNAzyme-induced signal cycle amplification strategy with Ag nanoparticles (NPs)-mediated liposomal immunoassay. Through sequential immunobinding, lysis treatment, and acidolysis, numerous Ag+ ions are released, and then they activate the DNAzyme, which further recycles the cleavage of hairpin DNA (HDNA) on the photoelectrode and induces signal cycle amplification. As a result, an ultralow detection limit (3.6 fg/mL) and a wide linear range (10-5-103 ng/mL) are achieved, which surpass those of most methods reported so far. The proposed sensing approach can be readily extended to detect various biomarkers by substituting the biorecognition events, providing great promise for biomedical and related applications.