Targeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy. Here, we report a core-shell type of nanoagent with iron (III) carboxylate metal-organic frameworks (MOFs) as shell while upconversion nanoparticles (UCNPs) as core, which enables near-infrared (NIR) light-triggered synergistically reinforced oxidative stress and calcium overload to mitochondria. The folate decoration on MOFs shells enables efficient cellular uptake of nanoagents. Based on the upconversion ability of UCNPs, NIR light mediates Fe³⁺-to-Fe²⁺ reduction and simultaneously activates the photoacid generator (pHP) encapsulated in MOFs cavities, which enables release of free Fe²⁺ and acidification of intracellular microenvironment, respectively. The overexpressed H₂O₂ in mitochondria, highly reactive Fe²⁺ and acidic milieu synergistically reinforce Fenton reactions for producing lethal hydroxyl radicals (•OH) while plasma photoacidification inducing calcium influx, leading to mitochondria calcium overload. The dual-mitochondria-damage-based therapeutic potency of the nanoagent has been unequivocally confirmed in cell- and patient-derived tumor xenograft models in vivo.

Long non-coding RNAs (lncRNAs) are under active investigation in the development of cancers including gastric cancer (GC). Oncogenic autophagy is required for cancer cell survival. The present study aimed to investigate the regulatory role of lncRNA small nucleolar host gene 11 (SNHG11) in GC. We show that SNHG11 is upregulated in GC, and that its upregulation correlated with dismal patient outcomes. Functionally, SNHG11 aggravated oncogenic autophagy to facilitate cell proliferation, stemness, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in GC. Mechanistically, SNHG11 post-transcriptionally upregulated catenin beta 1 (CTNNB1) and autophagy related 12 (ATG12) through miR-483-3p/miR-1276, while the processing of pre-miR-483/pre-miR-1276 was hindered by SNHG11. SNHG11 induced GSK-3β ubiquitination through interacting with Cullin 4A (CUL4A) to further activate the Wnt/β-catenin pathway. Intriguingly, SNHG11 regulated autophagy in a manner dependent upon ATG12 rather than the Wnt/β-catenin pathway, whereas SNHG11 contributed to the malignant behaviors of GC cells via both pathways. Finally, SNHG11 upregulation in GC cells was shown to be transcriptionally induced by TCF7L2. In conclusion, we reveal that SNHG11 is an onco-lncRNA in GC and might be a promising prognostic and therapeutic target for GC.

As membrane‐bound extracellular vesicles, exosomes have targeting ability for specific cell types, and the cellular environment strongly impacts their content and uptake efficiency. Inspired by these natural properties, the impacts of various cellular stress conditions on the uptake efficiency of tumor iterated exosomes are evaluated, and low‐pH treatment caused increased uptake efficiency and retained cell‐type specificity is found. Lipidomics analyses and molecular dynamics simulations reveal a glycerolipid self‐aggregation‐based mechanism for the enhanced homologous uptake. Furthermore, these low‐pH reprogrammed exosomes are developed into a smart drug delivery platform, which is capable of specifically targeting tumor cells and selectively releasing diverse chemodrugs in response to the exosome rupture by the near‐infrared irradiance‐triggered burst of reactive oxygen species. This platform exerts safe and enhanced antitumor effects demonstrated by multiple model mice experiments. These results open a new avenue to reprogram exosomes for smart drug delivery and potentially personalized therapy against their homologous tumor.