A cascade X-ray energy converting approach toward radio-afterglow cancer theranostics

Leveraging X-rays to initiate prolonged luminescence (radio-afterglow) and stimulate radiodynamic ¹O₂ production from optical agents provides opportunities for diagnosis and therapy at tissue depths inaccessible to light. However, X-ray-responsive organic luminescent materials are rare due to their intrinsic low X-ray conversion efficiency. Here we report a cascade X-ray energy converting approach to develop organic radio-afterglow nanoprobes (RANPs) for cancer theranostics. RANPs comprise a radiowave absorber that down-converts X-ray energy to emit radioluminescence, which is transferred to a radiosensitizer to produce singlet oxygen (¹O₂). ¹O₂ then reacts with a radio-afterglow substrate to generate an active intermediate that simultaneously decomposes to emit radio-afterglow. Through finetuning such a cascade, intraparticle radioluminescence energy transfer and the ¹O₂ transfer process, RANPs possess tunable wavelengths and long half-lives, and generate radio-afterglow and ¹O₂ at tissue depths of up to 15 cm. Moreover, we developed a biomarker-activatable nanoprobe (tRANP) that produces a tumour-specific radio-afterglow signal, leading to ultrasensitive detection and the possibility of surgical removal of diminutive tumours (1 mm³) under an X-ray dosage 20 times lower than inorganic materials. The efficient radiodynamic ¹O₂ generation of tRANP permits complete tumour eradication at an X-ray dosage lower than clinical radiotherapy and a drug dosage one to two orders of magnitude lower than most existing inorganic agents, leading to prolonged survival rates with minimized radiation-related adverse effects. Thus, our work reveals a generic approach to address the lack of organic radiotheranostic materials and provides molecular design towards precision cancer radiotherapy.