Photodynamic therapy (PDT) and photothermal therapies (PTTs) are both promising strategies for effective tumor therapy. However, the absence of O 2 at tumor sites hinders the sustained response of photosensitizers. Here, we develop a recycled cerium oxide (CeO 2 ) catalase nanozyme-loaded hyaluronic acid nanovesicle to address the hypoxic tumor microenvironments and targeted delivery of the photosensitizers [indocyanine green (ICG)] to tumors. A polysaccharide complex effectively modifies the surface of a polyethylenimine phenylboronic acid nanostructure to achieve the CeO 2 nanozyme-loading nanovesicles that exhibit both tumor-targeted enhancement and an improved hypoxic microenvironment. Also, the hydrogen peroxide responsiveness and acid-sensitive cleavage of phenylboronic acid specifically disintegrate the ICG/nanozyme coloaded nanovesicles in the tumor microenvironment. The in vitro synergistic tests and tumor suppression rate tests indicated that the cerium oxide nanozyme significantly improves the outcomes of PDT via ceriumelement valence state recycling and hypoxia improvement, thus enhancing the tumor suppression efficiency. This pH/H 2 O 2responsive nanozyme/ICG codelivery system provides a good carrier model for improving the tumor microenvironment and increasing the efficiency of tumor-targeted PTT and PDT therapies.

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.

Depression is the single largest contributor to the burden of disease, yet the current antidepressant medications are limited by high non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depression via direct projects to the lateral habenula (LHb) and the hypothalamus. Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons. Accordingly, modulation of LS-A2AR-positive neurons activity via optogenetic stimulation formatted depressive-like phenotype and the optogenetic activation of LS-A2AR-positive neurons projection terminals to the LHb or the hypothalamus, phenocopied depressive behaviors. Moreover, we shown a selective upregulation of A2AR in the LS in two mouse models of repeated stress-induced depression and in postmortem brains of suicide completers suffered from depression disorder, and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.