Cluster Missile‐Inspired Dynamic Nanocomposite Hydrogel Precisely Mediates Robust Locoregional Tumor Theranostics

Abstract Locoregional injectable tumoral theranostic nanocomposite hydrogels have shown great potential for clinical transformation, owing to their integration of the advantageous features of both systems, whilst simultaneously minimizing their drawbacks. However, how the nanomedicines efficiently escape from hydrogel and circumvent the intrinsically conflicting attributes between tumor penetration and accumulation directly determines the theranostic efficiency. Herein, a cluster missile‐inspired dynamic nanocomposite hydrogel synthesized via Schiff base reaction between crosslinked synergistic size‐changeable nano‐prodrugs (NPs) and glutaraldehyde (GA) is successfully developed. The hydrogel, analogous to a cluster missile, can efficiently release NPs with an initial size of 25.3 nm for deep tumor distribution and cellular internalization by responding to the tumoral extracellular pH, while precisely directing their exceptionally high cellular accumulation and highly selective drug release in response to the tumoral intracellular pH/glutathione (GSH), thereby achieving robust locoregional chemotherapy. Furthermore, platinum heavy metals within NPs confer upon the hydrogel an ability to spatiotemporally monitor dynamic changes in both itself and tumor tissues without necessitating additional conventional imaging agents. Thus, such a cluster missile‐inspired dynamic nanocomposite hydrogel paves the way toward clinical use for precise locoregional tumor theranostics.