Tumor Microenvironment Cascade‑Responsive Nanodrug with Self‑Targeting Activation and ROS Regeneration for Synergistic Oxidation‑Chemotherapy

Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop.The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate(MTX)self-assembles into nanoparticles(VSeM);decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time.Upon reaching tumor sites,acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake.Afterward,the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release;then the released VES could produce extra ROS to accelerate the collapse of VSeM.Finally,the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy.Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.

2D graphene oxide-L-arginine-soybean lecithin nanogenerator for synergistic photothermal and NO gas therapy

Nitric oxide(NO) gas therapy has been regarded as a promising strategy for cancer treatment. However,its therapeutic efficiency is still unsatisfying due to the limitations of monotherapy. Previous preclinical and clinical studies have shown that combination therapy could significantly enhance therapeutic efficiency. Herein, a graphene oxide(GO)-L-arginine(L-Arg, a natural NO donor) hybrid nanogenerator is developed followed by surface functionalization of soybean lecithin(SL) for synergistic enhancement of cancer treatment through photothermal and gas therapy. The resultant GO-Arg-SL nanogenerator not only exhibited good biocompatibility and excellent endocytosis ability, but also exhibited excellent photothermal conversion capability and high sensitivity to release NO within tumor microenvironment via inducible NO synthase(i NOS) catalyzation. Moreover, the produced hyperthermia and intracellular NO could synergistically kill cancer cells both in vitro and in vivo. More importantly, this nanogenerator can efficiently eliminate tumor while inhibiting the tumor recurrence because of the immunogenic cell death(ICD) elicited by NIR laser-triggered hyperthermia and the immune response activation by massive NO generation. We envision that the GO-Arg-SL nanogenerator could provide a potential strategy for synergistic photothermal and gas therapy.

Endogenous Fe^(2+)-activated ROS nanoamplifier for esterase-responsive and photoacoustic imaging-monitored therapeutic improvement

Chemodynamic therapy(CDT)is well acknowledged as potent reactive oxygen species(ROS)-mediated anticancer strategy.Especially,the study about labile iron pool(LIP)as endogenous ferrous catalyzer has paved the way for future CDT development.However,limited H_(2)O_(2) expression,mild acidity,reduced glutathione(GSH)ablation of ROS,etc.,all require employing alternate peroxo-complex to achieve enhanced CDT effect.As a non-Fenton-type substrate,artesunate(ART)has been utilized as a source of free radicals through decomposition of endoperoxide bridges catalyzed by ferrous ions,nonetheless,the non-tumor-specific delivery,inferior pharmacokinetics,and hydrophobic nature minimize the efficacy of ART in physiological systems.Herein,we devise a PPA nanoamplifier by conjugating ART with PEG-functionalized Pd@Pt nanoplates(PP NPs)to form ester linkage,ensuring specific intratumoral esterase-responsive ART release.Significantly,the PPA nanoamplifier combines the in situ decomposition of ARTs endoperoxide bridges by Fe^(2+) to superoxide anions(O_(2)^(·-))and peroxidase(POD)-like enzymatic catalysis of endogenous H_(2)O_(2) by PP to hydroxyl radicals(*OH),thus achieving amplified ROS-mediated tumor therapy.Besides,PPA displays GSH destruction potential,thereby protecting ROS from the cleavage by GSH oxidation.In addition,the strong absorption of PPA in near-infrared(NIR)region also endows PPA with photoacoustic property to realize imaging-guided CDT.In short,by taking advantages of the high enrichment and esterase-responsive drug release at tumor sites,PPA amplified ROS signals via dual pathways,killing tumor cells in vitro are inhibiting tumor growth in vivo,thereby realizing high-efficiency non-Fenton CDT.We believe our novel anti-tumor strategy based on PPA will broaden the future of ROS-mediated tumor-targeted therapy.