BACKGROUND Extracellular vesicles (EVs) contain a rich cargo of different RNA species with specialized functions and clinical applications. However, the landscape and characteristics of extracellular vesicle long RNA (exLR) in human blood remain largely unknown. METHODS We presented an optimized strategy for exLR sequencing (exLR-seq) of human plasma. The sample cohort included 159 healthy individuals, 150 patients with cancer (5 cancer types), and 43 patients with other diseases. Bioinformatics approaches were used to analyze the distribution and features of exLRs. Support vector machine algorithm was performed to construct the diagnosis classifier, and diagnostic efficiency was evaluated by ROC analysis. RESULTS More than 10000 exLRs, including mRNA, circRNA, and lncRNA, were reliably detected in each exLR-seq sample from 1–2 mL of plasma. We observed that blood EVs contain a substantial fraction of intact mRNAs and a large number of assembling spliced junctions; circRNA was also enriched in blood EVs. Interestingly, blood exLRs reflected their tissue origins and the relative fractions of different immune cell types. Additionally, the exLR profile could distinguish patients with cancer from healthy individuals. We further showed that 8 exLRs can serve as biomarkers for hepatocellular carcinoma (HCC) diagnosis with high diagnostic efficiency in training [area under the curve (AUC) = 0.9527; 95% CI, 0.9170–0.9883], validation cohort (AUC = 0.9825; 95% CI, 0.9606–1), and testing cohort (AUC = 0.9627; 95% CI, 0.9263–0.9991). CONCLUSIONS In summary, this study revealed abundant exLRs in human plasma and identified diverse specific markers potentially useful for cancer diagnosis.

Chemodynamic therapy (CDT) by introducing the Fenton-/Fenton-like reaction in an acidic and H 2 O 2 environment for toxic hydroxyl radical (•OH) generation, is a newly developed tumor-selective therapeutic. However, tumor acidosis, characterized by extracellular acidity (pH e ≈ 6.5) and intracellular alkalinity (pH i ≈ 7.2), undoubtedly confers a large chemical barrier for effective implementation of intracellular CDT and thus limits its functional activity and therapeutic efficacy. Here, the unique amorphous iron nanoparticles (AFeNPs) loaded with carbonic anhydrase IX inhibitor (CAI) are constructed to re-establish tumor acidosis with decreased pH i and increased pH e via inhibiting the over-expressed CA IX in cancer cells by CAI for self-enhanced CDT. The suppression of CA IX leads to H + accumulation in cells that could accelerate the AFeNPs-based Fenton reaction to drastically exacerbate oxidative stress in cells and subsequently induce cell death; meanwhile, the inhibition of H + formation outside cells efficiently represses the potential of tumor invasion and metastasis owing to the insufficient acidic ions for degradation of tumor extracellular matrix. Re-establishedtumor acidosis not only assists in the optimization of CDT, but also presents an opportunity for the development of new antitumor methods that are more tumor-acidity specific.

Chelating strategy and electron shuttle armed nanoagent for killing cancer cells at both an acidic and neutral pH with high CDT efficiency.

X-ray-induced photodynamic therapy (X-PDT) has high depth of penetration and has considerable potential for applications in cancer therapy. Scintillators and heavy metals have been adopted to absorb X-rays and transmit the energy to photosensitizers. However, the low efficiency of converting X-rays to reactive oxygen species (ROS) presents a challenge for the use of X-PDT to cure cancer. In this study, a new method based on LiLuF:Ce@SiO@AgPO@Pt(IV) nanoparticles (LAPNP) is presented that could be used to enhance the curative effects of X-PDT. To make full use of the fluorescence produced by nanoscintillators (LiLuF:Ce), a cisplatin prodrug Pt(IV) was utilized as a sacrificial electron acceptor to increase the yield of hydroxyl radicals (·OH) by increasing the separation of electrons and holes in photosensitizers (AgPO). Additionally, cisplatin is produced upon the acceptance of electrons by Pt(IV) and further enhances the damage caused by ·OH. Via two-step amplification, the potential of LAPNP to enhance the effects of X-PDT has been demonstrated.

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