The development of water-soluble aggregation-induced emission luminogens(AIEgens) emitting in the near-infrared (NIR) window holds promise for efficientbiomedical applications. Nevertheless, synthesizing water-soluble counterparts ofNIR AIEgens presents difficulties due to their intrinsic hydrophobic properties. Toaddress this issue, researchers have developed various molecular design strategiesto improve the water solubility of NIR AIEgens. The integration of hydrophilicgroups and targeting moieties is a crucial aspect of achieving precise photo-theranostics. Here, diverse approaches to attain water-soluble NIR AIEgens forbiomedical applications are presented, and three commonly used strategies thatinvolve decorating NIR AIEgens with positively or negatively charged groups,hydrophilic chains, and bioactive moieties are elaborated. These rational designstrategies are believed to provide solutions for enhancing the water solubility andbiological performance of NIR AIEgens in a single action. The remaining challengesand opportunities in thisfield are also discussed. The aim is to provide newinsights into the design of water-soluble NIR AIEgens and inspire more researchersto make significant contributions to this promising research area.PERSPECTIVEwww.small-science-journal.comSmall Sci.2023,3, 23000522300052 (1 of 16)© 2023 The Authors. Small Science published by Wiley-VCH GmbH