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.

Self-shrinking supramolecular nanoparticles syndicate energy suppression and NIR-II mild photothermal amplification of mitochondrial oxidative stress for breast cancer therapy

Photothermal therapy(PTT)may lead to healthy tissue damage,tumor metastasis,and recurrence,which makes mild photothermal therapy(mild PTT)stand out.However,overcoming heat resistance,insufficient therapeutic effect,and poor photothermal conversion efficiency has become new challenge.Herein,we report a dynamic supramolecular nanocarrier formed from amide-sericin and aldehyde-polyhydroxy glucan(denoted as SDA),the loose cavity of which can be filled by using the pharmaceutical combination of lonidamine(LND)and NIR-II photothermal agent of IR-1061,producing SDLI with a tighter inner hole,smaller and uniform particle size and excellent stability due to multiple pulling forces.Moreover,the intricate internal network structure prevents the hydrophobic IR-1061 from forming aggregates in the small cavity,and the photothermal conversion efficiency(PCE)can reach 48.9%.At the acidic tumor microenvironment of pH 6.5,the controlled release of LND can solve the problem of heat resistance of NIR-II mild PTT and significantly improve the therapeutic effect of NIR-II mild PTT.Meanwhile,SDLI also shows a reasonable tumor inhibition rate,so the synergistic strategy of inhibiting tumor energy metabolism and NIR-II mild PTT to magnify mitochondrial oxidative stress,continuous cell stress state-induced immunogenic cell death to promote the induction of tumor apoptosis is proposed to achieve more effective cancer treatment.

HDAC6 inhibitor loaded bimetallene nanosheets with antagonizing thermoresistance for augmented mild photothermal therapy

Photothermal therapy(PTT)induces thermoresistance through cellular heat shock response,which impairs the therapeutic efficacy of the PTT.To resolve this problem,we developed a photothermal theranostics(denoted as PMH),which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6(HDAC6)selected inhibitor(ACY-1215),showing the synergistic antitumor effect both in vitro and in vivo.Mechanistically,under the photoacoustic imaging(PA)navigation,the released ACY-1215 triggered by NIR laser irradiation decrease the heat shock proteins(HSPs)expression and weaken the HDAC6-regulated HSP90 deacetylation,thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway.Moreover,mild photothermal therapy(mPTT)treatment compromised the autophagy,which induced by HDAC6 inhibition,leading to mPTTinduced misfolded or unfold proteins further accumulation.Given that inhibition of HDAC6 plus m PTT contribute to tumor eradication.This study develops a promising combination strategy based on m PTT for future cancer treatment.

Robust boron nanoplatform provokes potent tumoricidal activities via inhibiting heat shock protein

Near-infrared(NIR)-light-triggered photothermal therapy(PTT)is a promising treatment for breast cancer.However,its therapeutic efficiency is often compromised due to the heatinduced up-regulation of heat shock proteins,which confer photothermal resistance.To solve this urgent problem,PEGylated two-dimensional boron nanosheets(B-PEG)-which allow both multimodal imaging and photothermal conversion-were loaded with gambogic acid(GA),which can inhibit heat shock protein 90(Hsp90).Experimental findings indicated that this combination of B-PEG and GA could serve as an integrated drug delivery system for cancer diagnosis and treatment.It could be used to administer mild PTT as well as chemotherapy for breast cancer,provide improved anti-tumor effects,and reduce the toxicity of PTT,all while inhibiting breast cancer growth.This drug delivery system could offer a novel tool for administering chemotherapy combined with PTT while avoiding the adverse effects of traditional PTT.

Novel nanocarrier for promoting tumor synergistic therapy by down-regulation of heat shock proteins and increased Fe^(3+) supply

With the emergence of new therapeutic methods,synergistic therapy has attracted great attention because it can improve the treatment efficacy,and reduce the toxic side effects.Herein,we developed a nanocarrier BGT by co-loading glucose oxidase(GOD)and transferrin(TRF)on the porous Bi nanoparticles(NPs)for improving tumor synergistic therapy.GOD endows BGT with catalytic capacity of decomposing glucose into gluconic acid and a large amount of H2O2 for starving therapy.H2O2 further destroys TRF structure and releases Fe^(3+),which could react with H2O2 to generate highly toxic·OH for chemodynamic therapy(CDT).In addition,GOD-induced glucose depletion and decreased expression of heat shock proteins(HSPs)can also alleviate the thermotolerance of tumor cells to improve the efficiency of mild photothermal therapy(PTT).Mild temperature can in turn promote the production of reactive oxygen species(ROS)for improving the synergistic therapy.Combined with the excellent targeting ability of TRF,efficient tumor synergistic therapy can be achieved.This work shows that BGT has good photothermal stability and biocompatibility,and can be used as a nanocarrier,providing an effective method for collaborative therapy of tumor.