NIR-Ⅱ成像引导的精准光动力治疗通过干扰糖代谢重编程增强肿瘤饥饿治疗

Metabolic reprogramming is a mechanism by which cancer cells alter their metabolic patterns to promote cell proliferation and growth, thereby enabling their resistance to external stress. 2-Deoxy-Dglucose(2DG) can eliminate their energy source by inhibiting glucose glycolysis, leading to cancer cell death through starvation. However, a compensatory increase in mitochondrial metabolism inhibits its efficacy. Herein, we propose a synergistic approach that combines photodynamic therapy(PDT) with starvation therapy to address this challenge. To monitor the nanodrugs and determine the optimal triggering time for precise tumor therapy, a multifunctional nano-platform comprising lanthanide-doped nanoparticle(Ln NP) cores was constructed and combined with mesoporous silicon shells loaded with2DG and photosensitizer chlorin e6(Ce6) in the mesopore channels. Under 980 nm near-infrared light excitation, the downshifted 1550 nm fluorescence signal in the second near-infrared(NIR-II, 1000–1700 nm) window from the Ln NPs was used to monitor the accumulation of nanomaterials in tumors.Furthermore, upconverted 650 nm light excited the Ce6 to generate singlet oxygen for PDT, which damaged mitochondrial function and enhanced the efficacy of 2DG by inhibiting hexokinase 2 and lactate dehydrogenase A expressions. As a result, glucose metabolism reprogramming was inhibited and the efficiency of starvation therapy was significantly enhanced. Overall, the proposed NIR-II bioimaging-guided PDT-augmented starvation therapy, which simultaneously inhibited glycolysis and mitochondria, facilitated the effects of a cancer theranostic system.

Activation of autophagy by in situ Zn^(2+) chelation reaction for enhanced tumor chemoimmunotherapy

Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death(ICD),a process in which tumor cells convert from nonimmunogenic to immunogenic forms.However,the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment.Although autophagy is involved in activating tumor immunity,the synergistic role of autophagy in ICD remains elusive and challenging.Herein,we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion(Zn^(2+))-doped,disulfiram(DSF)-loaded mesoporous silica nanoparticles(DSF@Zn-DMSNs).Upon pH-sensitive biodegradation of DSF@Zn-DMSNs,Zn2+and DSF are coreleased in the mildly acidic tumor microenvironment,leading to the formation of toxic Zn2+chelate through an in situ chelation reaction.Consequently,this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns(DAMPs)but also activates autophagy,which mediates the amplified release of DAMPs to enhance ICD.In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy,thus enhancing immunotherapy by promoting the infiltration of T cells.This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.

Destroying pathogen-tumor symbionts synergizing with catalytic therapy of colorectal cancer by biomimetic protein-supported single-atom nanozyme

The crucial role of intratumoral bacteria in the progression of cancer has been gradually recognized with the development of sequencing technology.Several intratumoral bacteria which have been identified as pathogens of cancer that induce progression,metastasis,and poor outcome of cancer,while tumor vascular networks and immunosuppressive microenvironment provide shelters for pathogens localization.Thus,the mutually-beneficial interplay between pathogens and tumors,named“pathogentumor symbionts”,is probably a potential therapeutic site for tumor treatment.Herein,we proposed a destroying pathogen-tumor symbionts strategy that kills intratumoral pathogens,F.nucleatum,to break the symbiont and synergize to kill colorectal cancer(CRC)cells.This strategy was achieved by a groundbreaking protein-supported copper single-atom nanozyme(BSA-Cu SAN)which was inspired by the structures of native enzymes that are based on protein,with metal elements as the active center.BSA-Cu SAN can exert catalytic therapy by generating reactive oxygen species(ROS)and depleting GSH.The in vitro and in vivo experiments demonstrate that BSA-Cu SAN passively targets tumor sites and efficiently scavenges F.nucleatum in situ to destroy pathogentumor symbionts.As a result,ROS resistance of CRC through elevated autophagy mediated by F.nucleatum was relieved,contributing to apoptosis of cancer cells induced by intracellular redox imbalance generated by BSA-Cu SAN.Particularly,BSA-Cu SAN experiences renal clearance,avoiding long-term systemic toxicity.This work provides a feasible paradigm for destroying pathogen-tumor symbionts to block intratumoral pathogens interplay with CRC for antitumor therapy and an optimized trail for the SAN catalytic therapy by the clearable protein-supported SAN.