Toward Drift-Free High-Throughput Nanoscopy Through Adaptive Intersection Maximization

Single-molecule localization microscopy (SMLM) often suffers from suboptimal resolution due to imperfect drift correction. Existing marker-free drift correction algorithms often struggle to reliably track high-frequency drift and lack the computational efficiency to manage large, high-throughput localization datasets. We present an adaptive intersection maximization-based method (AIM) that leverages the entire dataset’s information content to minimize drift correction errors, particularly addressing high-frequency drift, thereby enhancing the resolution of existing SMLM systems. We demonstrate that AIM can robustly and efficiently achieve an angstrom-level tracking precision for high-throughput SMLM datasets under various imaging conditions, resulting in an optimal resolution in simulated and biological experimental datasets. We offer AIM as one simple, model-free software for instant resolution enhancement with standard CPU devices.