Intracellular Manipulation by Particle Swarm Optimized Optical Tweezers

ABSTRACT Optically intracellular manipulation and sensing, both in vivo and in vitro, face fundamental challenges due to spatially varying aberrations arising from refractive index heterogeneity and dynamic organelle motion. Achieving high‐speed laser field optimization to correct aberrations is essential but remains challenging. Here, we develop a particle swarm optimized optical tweezers (PSOOT) employing a multimodal synergistic strategy to enhance both the speed and performance of trapping beam optimization. Leveraging fluorescence feedback to dynamically and simultaneously modulate Zernike aberration modes enables faster convergence to the target intensity levels through multimodal coordination. In numerical simulation, this strategy can find the potential solutions at a speed more than four times faster than the traditional scanning method. Experimentally, PSOOT achieves an order‐of‐magnitude enhancement in trap stiffness for 1 µm spheres, increasing k x from 0.30 to 3.36 pN/µm/mW and for 110 nm particles in aqueous solution, from 0.11 to 0.34 pN/µm/mW, approaching the theoretical limit for such trapped objects. The optimized optical trap enables the stable trapping and optical‐driven manipulation of a single lipid droplet in living HeLa cells. Furthermore, the spatial intracellular heterogeneity of aberrations is quantitatively investigated. The methodology establishes a new paradigm for closed‐loop optical tweezers in biological environments, which may advance the mechanobiology studies, such as intracellular targeted delivery and cellular surgery.