Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy

Ultrahigh dose-rate(FLASH)radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity.However,tumor recurrence largely impede the effectiveness of FLASH therapy.Overcoming tumor recurrence is crucial for practical FLASH applications.Here,we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent(TPE-BBT)and a glutaminase inhibitor(CB-839).Within nanoparticles,TPE-BBT exhibits aggregation-induced emission peaked at 900 nm,while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability.The balanced photothermal effect and photoluminescence are ideal for phototheranostics.Upon 660-nm laser irradiation,the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy,jointly inhibiting homologous recombination repair of DNA.The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity.This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy,and provides novel recurrence-resistant radiotherapy without adverse side effects.

Matthew effect:General design strategy of ultra-fluorogenic nanoprobes with amplified dark–bright states in aggregates

Fluorescence imaging,a key technique in biological research,frequently utilizes fluorogenic probes for precise imaging in living systems.Tetrazine is an effective emission quencher in fluorogenic probe designs,which can be selectively damaged upon bioorthogonal click reactions,leading to considerable emission enhancement.Despite significant efforts to increase the emission enhancement ratio(I_(AC)/I_(BC))of tetrazine-functionalized fluorogenic probes,the influence of molecular aggregation on the emission properties has been largely overlooked in these probe designs.In this study,we reveal that an ultrahigh I_(AC)/I_(BC)can be realized in the aggregate system when tetrazine is paired with aggregation-induced emission(AIE)luminogens.Tetrazine amplifies its quenching efficiency upon aggregation and drastically reduce background emissions.Subsequent click reactions damage tetrazine and trigger significant AIE,leading to considerably enhanced I_(AC)/I_(BC).We further showcase the capability of these ultra-fluorogenic systems in selective imaging of multiple organelles in living cells.We term this unique fluorogenicity of AIE luminogen-quencher complexes with amplified dark-bright states as“Matthew effect”in aggregate emission,potentially providing a universal approach to attain ultrahigh I_(AC)/I_(BC)in diverse fluorogenic systems.