No abstract

Primary cilia extending from mother centrioles are essential for vertebrate development and homeostasis maintenance. Centriolar coiled-coil protein 110 (CP110) has been reported to suppress ciliogenesis initiation by capping the distal ends of mother centrioles. However, the mechanism underlying the specific degradation of mother centriole-capping CP110 to promote cilia initiation remains unknown. Here, we find that autophagy is crucial for CP110 degradation at mother centrioles after serum starvation in MEF cells. We further identify NudC-like protein 2 (NudCL2) as a novel selective autophagy receptor at mother centrioles, which contains an LC3-interacting region (LIR) motif mediating the association of CP110 and the autophagosome marker LC3. Knockout of NudCL2 induces defects in the removal of CP110 from mother centrioles and ciliogenesis, which are rescued by wild-type NudCL2 but not its LIR motif mutant. Knockdown of CP110 significantly attenuates ciliogenesis defects in NudCL2-deficient cells. In addition, NudCL2 morphants exhibit ciliation-related phenotypes in zebrafish, which are reversed by wild-type NudCL2, but not its LIR motif mutant. Importantly, CP110 depletion significantly reverses these ciliary phenotypes in NudCL2 morphants. Taken together, our data suggest that NudCL2 functions as an autophagy receptor mediating the selective degradation of mother centriole-capping CP110 to promote ciliogenesis, which is indispensable for embryo development in vertebrates.

Tumor-associated macrophages (TAMs), the most abundant immune cells in the tumor microenvironment (TME), profoundly affect the occurrence and development of tumors. To overcome the common limitations of TAMs-targeted delivery systems, such as off-target toxicity, high cost, and transformation probability, we fabricated pirarubicin (THP)-loaded palmitic acid modified human serum albumin nanoparticles (THP-PSA NPs) for dual-targeting of tumor cells and TAMs via acidic secretory proteins rich in cysteine (SPARC) and scavenger receptor-A (SR-A), respectively. In vitro, the THP-PSA NPs exhibit stronger cytotoxicity against 4T1 and M2 macrophages compared with THP-loaded human serum albumin nanoparticles (THP-HSA NPs). In vivo, the infiltration of myeloid-derived suppressor cells (MDSCs) and the secretion of immunosuppressive cytokines significantly decrease after effective elimination of the TAMs through the THP-PSA NPs treatment; this is accompanied by an increase in the immunostimulatory cytokine expression level. Moreover, the antitumor and antimetastasis experimental results indicate that the tumor volumes in mice treated with the THP-PSA NPs are effectively controlled, resulting in an inhibition rate of 81.0% and almost no metastases in the lung tissues. Finally, in terms of biological safety, the THP-PSA NPs perform similar to THP-HSA NPs, causing no damage to the liver or kidney.

Chondroitin sulfate-mediated albumin corona nanoparticles were readily prepared without any chemical reaction, and their active tumor targeting and therapeutic effects were examined. Negatively charged chondroitin sulfate (CS) and positively charged doxorubicin (DOX) self-assembled into nanoparticles (CS-DOX-NPs) via electrostatic interactions. Bovine serum albumin (BSA) was then adsorbed on the surface of CS-DOX-NPs to form albumin corona nanoparticles (BC-DOX-NPs) protected from endogenous proteins. Due to the dual effect of BSA and CS, BC-DOX-NPs interacted with the gp60, SPARC and CD44 receptors on tumor cells, facilitating their rapid and efficient transcytosis and improving their accumulation and uptake within tumor tissues. The simultaneous presence of BSA and CS also allowed BC-DOX-NPs to target CD44 efficiently, leading to greater cellular uptake and cytotoxicity against 4T1 cells than CS-DOX-NPs or free DOX. Intravenous injection of BC-DOX-NPs into orthotopic 4T1 tumor-bearing mice led to greater drug accumulation at the tumor site than with CS-DOX-NPs or free DOX, resulting in significant inhibition of tumor growth and lower exposure of major organs to the drug.

The etiology of chronic kidney disease (CKD) is complex and diverse, which could be briefly categorized to glomerular- or tubular-originated. However, the final outcomes of CKD are mainly glomerular sclerosis, endothelial dysfunction and injury, and chronic inflammation. Thus, targeted delivery of drugs to the glomeruli in order to ameliorate glomerular endothelial damage may help alleviate CKD and help enrich our knowledge. The herb tripterygium wilfordii shows therapeutic effect on kidney disease, and celastrol (CLT) is one of its active ingredients but with strong toxicity. Therefore, based on the unique structure and pathological characteristics of the glomerulus, we designed a targeted delivery system named peptides coupled CLT-phospholipid lipid nanoparticles (PC-PLNs) to efficiently deliver CLT to damaged endothelial cells and podocytes in the glomerulus for CKD treatment and research. PC-PLNs could effectively inhibit inflammation, reduce endothelial damage, alleviate CKD severity, and reduce the toxicity of CLT. We also studied the mechanism of CLT in the treatment of nephropathy and found that CLT can increase the level of NO by increasing eNOS while inhibiting the expression of VCAM-1, thus provides an anti-inflammatory effect. Therefore, our study not only offered an efficient CKD drug formulation for further development, but also provided new medical knowledge about CKD. Electronic Supplementary Material Supplementary material (attached with all the supporting tables and figures mentioned in this work) is available in the online version of this article at 10.1007/s12274-021-3894-x.