Programmable manganese-chalcogen coordination nanoregulator enables dual-lock prodrug activation through electron cloud engineering for synergistic chemo-metalloimmunotherapy

Hybrid chalcogen bonds bridged homodimer prodrug nanoassemblies demonstrated excellent self-assembly stability, sensitive redox responsiveness, and high drug delivery efficiency. However, nonadjustable high sensitivity of hybrid chalcogen bonds was usually accompanied by oxidative instability in the oxygen-rich systemic circulation, which limited their efficacy. To address this dilemma, we developed Mn 2+ -coordinated homodimer prodrug nanoassemblies. The coordination between Mn 2+ and chalcogen (Te, Se, S) mediated electron cloud redistribution through d-orbital hybridization, facilitating electron sharing. This electronic delocalization reduced the electron density surrounding chalcogen centers, improving their chemical stability and the pharmacokinetic properties of prodrugs. This coordination complex acted as a programmable dual-lock activation nanoregulator: (1) pH-sensitive cleavage of Mn 2+ coordination bonds within the tumor microenvironment mediated nanostructural disassembly, followed by (2) GSH/ROS-responsive prodrug release. Critically, the sequential activation mechanism maintained systemic inertness in normal tissues while exhibiting superior activation efficiency within tumors. Meanwhile, Mn 2+ activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, enhancing antigen presentation and immune responses for a combined chemoimmunotherapeutic effect. This work proposed the reasonable design and construction of the metal-coordinated homodimer prodrug nanoassemblies based on the interactions between chalcogen of linkers and metal atoms, opening up new opportunities for developing more effective cancer therapeutics.