Exosomes or small extracellular vesicles are considered a new generation of bioinspired-nanoscale drug delivery system (DDS). Endogenous exosomes function as signalosomes since they convey signals via ligands or adhesion molecules located on the exosomal membrane, or packaged inside the exosome. Recently, exosome membrane modification, therapeutic payloads encapsulation, and modulation of in vivo disposition of exosomes have been extensively investigated, among which significant advances have been made to optimize exosome-mediated delivery to solid tumors. Exosomes, specifically tumor cell-derived exosomes, are presumed to have tumor-preferential delivery due to the homotypic features. However, quality attributes that dictate the tissue distribution, cell type-selective uptake, and intracellular payload release of the administered exosomes, as well as the spatiotemporal information regarding exosome fate in vivo, remain to be further investigated. This review summarizes recent advances in developing exosomes as drug delivery platforms with a focus on tumor targeting. The pharmacokinetic features of naive exosomes and factors influencing their intracellular fate are summarized. Recent strategies to improve tumor targeting of exosomes are also reviewed in the context of the biological features of tumor and tumor microenvironment (TME). Selected approaches to augment tumor tissue deposition of exosomes, as well as methods to enhance intracellular payload delivery, are summarized with emphasis on the underlying mechanisms (eg, passive or active targeting, endosomal escape, etc.). In conclusion, this review highlights recently reported tumor-targeting strategies of exosome-based drug delivery, and it’s in the hope that multiple approaches might be employed in a synergistic combination in the development of exosome-based cancer therapy.

Emerging evidence suggests that the sterile alpha‐motif (SAM) and histidine‐aspartate (HD) domain‐containing protein 1 (SAMHD1) is implicated in various cancers, including hepatocellular carcinoma (HCC). However, its precise role in tumor cells and the underlying mechanisms remain unclear. This study aimed to investigate the expression patterns, prognostic values, and functional role of SAMHD1 in HCC progression. We constructed liver tissue microarrays using tumor and paired paratumor tissue specimens from 187 patients with primary HCC. Our findings indicate that nuclear SAMHD1 protein levels are increased in tumors compared to paratumor tissues. Moreover, nuclear SAMHD1 levels decline in advanced tumor stages, with higher SAMHD1 nuclear staining correlating with favorable prognostic outcomes. Hepatocyte‐specific SAMHD1 knockout mice, generated by crossing SAMHD1 ^fl/fl mice with Alb‐cre mice, showed accelerated tumor progression in a diethylnitrosamine (DEN)‐induced HCC model. In hepatoma cell lines, nuclear overexpression of SAMHD1 inhibited cell proliferation by stalling mitosis, independent of its deoxynucleotide triphosphohydrolase (dNTPase) function. Mechanistically, SAMHD1 interacts with the cohesin complex in nucleus, enhancing sister chromatid cohesion during cell division, which delays metaphase progression. Our findings suggest that nuclear SAMHD1 plays a critical role in slowing HCC progression by regulating mitosis, highlighting its potential as a therapeutic target by manipulating cohesin dynamics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disorders and a growing public health concern. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, is known for its roles in nucleotide metabolism, antiviral defense, and immune regulation, but its function in hepatocytes and contribution to MASLD pathogenesis remain unclear. In this study, we observed that hepatic SAMHD1 expression was markedly increased in MASLD patient samples and diet-induced MASLD mouse models. In vitro, mimicking MASLD-associated dyslipidemia with palmitic acid, oleic acid, and cholesterol upregulated SAMHD1 expression, an IFN-γ-induced protein, accompanied by increased IFN-γ receptor 1 expression and STAT1 activation in HepG2 cells. Functional studies using SAMHD1-overexpressing and knockdown hepatic cell lines, as well as hepatocyte-specific AAV-mediated SAMHD1 overexpression in vivo, demonstrated that SAMHD1 promoted lipid droplet accumulation. Conversely, hepatocyte-specific SAMHD1 knockout reduced steatosis and liver injury in diet-induced MASLD mouse models. Mechanistically, SAMHD1 enhanced the proteolytic activation of SREBP1 and SREBP2 by upregulating SCAP, S1P, and S2P in a cohesin complex-dependent manner. Collectively, these findings identify hepatocyte SAMHD1 as a promoter of liver steatosis through SREBP activation and highlight it as a potential therapeutic target for MASLD.