Ion‑Programmed In Situ J‑Aggregates Overcome Concentration‐Dependence for On‐Demand Phototherapy of Diabetic Bacterial Infections

J‐aggregates are attractive for phototheranostics due to their enhanced absorption, redshift, and photostability, but they typically require high dye concentrations or nanocarriers. Inspired by Derjaguin–Landau–Verwey–Overbeek (DLVO) theory, in which multivalent ions promote colloid coagulation by compressing the electrical double layer and reducing electrostatic repulsion (Schulze–Hardy rule: CCC ∝ 1/z 6 ), we developed a strategy based on long‐range electrostatic interactions to construct high‑valent‑ion‐programmable J‐aggregates. By meso‑substituting positive or negative charged moieties to an anionic pentamethine cyanine (ACy5) to manipulate its stacking preference in ionic environment, we obtained probes capable of undergoing sharp J‑aggregation in response to high‑valent counterions (z ≥ 2). Benefiting from the long‑range nature of electrostatic interactions, ACy5‐Py‐3Py exhibited anti‐concentration‑dependent assembly and formed stable J‑aggregates even at concentrations as low as 0.25 µM. Taking advantage of the multivalent‐anion‐rich bacterial membrane, we used ACy5‐Py‐3Py to achieve in situ J‐aggregation on bacterial surfaces. The resulting aggregates exhibit potent phototherapeutic activity, enabling efficient bacterial theranostics and outperforming vancomycin in healing MRSA‐infected wounds in diabetic mice. No adverse effects were observed in sterile wounds, confirming high biocompatibility. Together with its specific bactericidal efficacy, ACy5‑Py‑3Py represents a promising on‑demand phototheranostic J‑aggregate agent.