"Artificial Lighthouse" Overcomes Tumor Microenvironment Heterogeneity's "Sea Fog": Pre-Targeted Strategy-Mediated Nanomedicine Enables Tumor Body Fluid Detection, In Vivo Imaging, and Multitherapy Treatment.

Nanomedicine has broad prospects in tumor diagnosis and treatment, but its clinical translation has long been limited by targeted delivery efficiency. The heterogeneity of the tumor microenvironment is like a "sea fog" that hinders precision medicine. This makes it difficult for traditional active targeting that relies on natural targets to achieve precise delivery. For this difficulty, this review summarizes the constraints of tumor microenvironment heterogeneity on nanomaterials in terms of time and space. Pre-targeting strategies enhance delivery efficiency by constructing an "artificial lighthouse." According to the source of the target and the mode of specific binding, this review divides pre-targeting strategies into two categories: biomolecular recognition-mediated and bioorthogonal click chemistry-mediated. On this basis, this review comprehensively introduces recent progress in pre-targeting-enabled nanomedicine in body fluid-based detection, in vivo imaging, and multi-therapies. Furthermore, this review is the first to summarize the synergistic mechanisms of pre-targeting with prodrugs, insitu self-assembly, and dual-targeting strategies. This review systematically summarizes the complete framework of pre-targeting strategies, from mechanisms and classifications to applications and expansions. It aims to provide inspiration for the development of nanomedicine in the field of oncology for effective cancer diagnosis and treatment.