Tumor innervation is a common phenomenon with unknown mechanism. Here, we discovered a direct mechanism of tumor-associated macrophage (TAM) for promoting de novo neurogenesis via a subset showing neuronal phenotypes and pain receptor expression associated with cancer-driven nocifensive behaviors. This subset is rich in lung adenocarcinoma associated with poorer prognosis. By elucidating the transcriptome dynamics of TAM with single-cell resolution, we discovered a phenomenon “macrophage to neuron-like cell transition” (MNT) for directly promoting tumoral neurogenesis, evidenced by macrophage depletion and fate-mapping study in lung carcinoma models. Encouragingly, we detected neuronal phenotypes and activities of the bone marrow–derived MNT cells (MNTs) in vitro. Adoptive transfer of MNTs into NOD/SCID mice markedly enhanced their cancer-associated nocifensive behaviors. We identified macrophage-specific Smad3 as a pivotal regulator for promoting MNT at the genomic level; its disruption effectively blocked the tumor innervation and cancer-dependent nocifensive behaviors in vivo. Thus, MNT may represent a precision therapeutic target for cancer pain.

Multicellular spheroids have served as a promising preclinical model for drug efficacy testing and disease modeling. Many microfluidic technologies, including those based on water–oil–water double emulsions, have been introduced for the production of spheroids. However, sustained culture and the in situ characterization of the generated spheroids are currently unavailable for the double emulsion-based spheroid model. This study presents a streamlined workflow, termed the double emulsion-pretreated microwell culture (DEPMiC), incorporating the features of (1) effective initiation of uniform-sized multicellular spheroids by the pretreatment of double emulsions produced by microfluidics without the requirement of biomaterial scaffolds; (2) sustained maintenance and culture of the produced spheroids with facile removal of the oil confinement; and (3) in situ characterization of individual spheroids localized in microwells by a built-in analytical station. Characterized by microscopic observations and Raman spectroscopy, the DEPMiC cultivated spheroids accumulated elevated lipid ordering on the apical membrane, similar to that observed in their Matrigel counterparts. Made possible by the proposed technological advancement, this study subsequently examined the drug responses of these in vitro-generated multicellular spheroids. The developed DEPMiC platform is expected to generate health benefits in personalized cancer treatment by offering a pre-animal tool to dissect heterogeneity from individual tumor spheroids.

Liquid–liquid droplet reactors have garnered significant interest in biochemical applications by simulating thermodynamic systmes, ranging from closed systems, semi-closed/semi-open systems, to open systems.

The past decade has witnessed a significant development of droplet microfluidics for applications such as directed evolution and single-cell analysis. While the stability and manipulation of droplets are part of the prerequisites to further their applications, most of the currently available surfactants serve solely as stabilizers between the interfaces of water and oil. In this study, we present a novel type of photo-responsive fluorosurfactant based on fluorinated plasmonic nanoparticles (NPs). The demonstration by fluorinated gold–silica core–shell NPs (f-Au@SiO2) has been shown to be effective in stabilizing the water-in-fluorocarbon oil droplets. More importantly, the photothermal response enabled by the f-Au@SiO2 has been shown to be promising for the movement of droplets as well as the alteration of interfacial stability. The unique photo-responsiveness provided by the plasmonic NPs is expected to gear up the droplet microfluidics with an “active” surfactant for reconfigurable optical manipulation.

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