Chimeric antigen receptor‐T (CAR‐T) cell immunotherapy has shown impressive clinical outcomes for hematologic malignancies. However, its broader applications are challenged due to its complex ex vivo cell‐manufacturing procedures and low therapeutic efficacy against solid tumors. The limited therapeutic effects are partially due to limited CAR‐T cell infiltration to solid tumors and inactivation of CAR‐T cells by the immunosuppressive tumor microenvironment. Here, a facile approach is presented to in vivo program macrophages, which can intrinsically penetrate solid tumors, into CAR‐M1 macrophages displaying enhanced cancer‐directed phagocytosis and anti‐tumor activity. In vivo injected nanocomplexes of macrophage‐targeting nanocarriers and CAR‐interferon‐γ‐encoding plasmid DNA induce CAR‐M1 macrophages that are capable of CAR‐mediated cancer phagocytosis, anti‐tumor immunomodulation, and inhibition of solid tumor growth. Together, this study describes an off‐the‐shelf CAR‐macrophage therapy that is effective for solid tumors and avoids the complex and costly processes of ex vivo CAR‐cell manufacturing.

Intervertebral disc (IVD) degeneration (IVDD) is a leading cause of chronic low backpain. There is a strong clinical demand for more effective treatments for IVDD as conventional treatments provide only symptomatic relief rather than arresting IVDD progression. This study shows that senolytic therapy with local drug delivery can inhibit IVDD and restore IVD integrity. ABT263, a senolytic drug, is loaded in poly(lactic-co-glycolic acid) nanoparticles (PLGA-ABT) and intradiscally administered into injury-induced IVDD rat models. The single intradiscal injection of PLGA-ABT may enable local delivery of the drug to avascular IVD, prevention of potential systemic toxicity caused by systemic administration of senolytic drug, and morbidity caused by repetitive injections of free drug into the IVD. The strategy results in the selective elimination of senescent cells from the degenerative IVD, reduces expressions of pro-inflammatory cytokines and matrix proteases in the IVD, inhibits progression of IVDD, and even restores the IVD structure. This study demonstrates for the first time that local delivery of senolytic drug can effectively treat senescence-associated IVDD. This approach can be extended to treat other types of senescence-associated degenerative diseases.

Although T‐cell therapy is a remarkable breakthrough in cancer immunotherapy, the therapeutic efficacy is limited for solid tumors. A major cause of the low efficacy is T‐cell exhaustion by immunosuppressive mechanisms of solid tumors, which are mainly mediated by programmed death‐ligand 1 (PD‐L1) and transforming growth factor‐beta (TGF‐β). Herein, T‐cell‐derived nanovesicles (TCNVs) produced by the serial extrusion of cytotoxic T cells through membranes with micro‐/nanosized pores that inhibit T‐cell exhaustion and exhibit antitumoral activity maintained in the immunosuppressive tumor microenvironment (TME) are presented. TCNVs, which have programmed cell death protein 1 and TGF‐β receptor on their surface, block PD‐L1 on cancer cells and scavenge TGF‐β in the immunosuppressive TME, thereby preventing cytotoxic‐T‐cell exhaustion. In addition, TCNVs directly kill cancer cells via granzyme B delivery. TCNVs successfully suppress tumor growth in syngeneic‐solid‐tumor‐bearing mice. Taken together, TCNV offers an effective cancer immunotherapy strategy to overcome the tumor's immunosuppressive mechanisms.

Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.

Despite the clinically proven efficacies of immune checkpoint blockades, including anti‐cytotoxic T lymphocyte‐associated protein 4 antibody (αCTLA‐4), the low response rate and immune‐related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA‐4 therapy are mainly due to the suboptimal activation of tumor‐specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA‐4 is delivered by dendritic cell‐derived nanovesicles presenting tumor antigens (DCNV‐TAs) that exclusively interact with tumor‐specific T cells, leading to selective activation of tumor‐specific CTLs. Compared to conventional αCTLA‐4 therapy, treatment with αCTLA‐4‐conjugated DCNV‐TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor‐bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA‐4 and tumor antigens enables selective activation of tumor‐specific T cells and potentiates the antitumor efficacy of αCTLA‐4 without inducing systemic irAEs.