Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications in protein structure and functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal and spatial roles, thereby associating AS with standard biological activities and diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role in regulating alternative splicing events. Under physiological conditions, the diversity of proteins mediated by AS influences the structure, function, interaction, and localization of proteins, thereby participating in the differentiation and development of an array of tissues and organs. Under pathological conditions, alterations in AS are linked with various diseases, particularly cancer. These changes can lead to modifications in gene splicing patterns, culminating in changes or loss of protein functionality. For instance, in cancer, abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes, thereby promoting the onset and progression of tumors. AS and RBPs are also associated with numerous neurodegenerative diseases and autoimmune diseases. Consequently, the study of AS across different tissues holds significant value. This review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases, which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a "cold" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (PD-L1) transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8⁺ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.

Targeted drug delivery using micro-nano robots (MNRs) is a rapidly advancing and promising field in biomedical research. MNRs enable precise delivery of drugs, addressing a wide range of healthcare needs. However, the application of MNRs in vivo is limited by power issues and specificity in different scenarios. Additionally, the controllability and biological safety of MNRs must be considered. To overcome these challenges, researchers have developed bio-hybrid micro-nano motors that offer improved accuracy, effectiveness, and safety for targeted therapies. These bio-hybrid micro-nano motors/robots (BMNRs) use a variety of biological carriers, blending the benefits of artificial materials with the unique features of different biological carriers to create tailored functions for specific needs. This review aims to give an overview of the current progress and application of MNRs with various biocarriers, while exploring the characteristics, advantages, and potential hurdles for future development of these bio-carrier MNRs.

Using micro/nanorobots (MNRs) for targeted therapy within the human body is an emerging research direction in biomedical science. These nanoscale to microscale miniature robots possess specificity and precision that are lacking in most traditional treatment modalities. Currently, research on electrically controlled micro/nanorobots is still in its early stages, with researchers primarily focusing on the fabrication and manipulation of these robots to meet complex clinical demands. This review aims to compare the fabrication, powering, and locomotion of various electrically controlled micro/nanorobots, and explore their advantages, disadvantages, and potential applications.

Acute myeloid leukemia (AML) is an aging-related malignancy, with patients aged ≥60 years old facing significantly poorer prognosis. Umbilical cord blood (UCB) has emerged as a promising source with effective anti-aging roles. Here, we conducted a prospective, phase 2, single-arm trial of UCB infusion as an adjuvant consolidation therapy in elderly AML patients (ChiCTR-OPC-15006492). A total of 51 patients were enrolled (median age 66 years; range, 60–75) and received two cycles of consolidation chemotherapy combined with UCB infusion. At a median follow-up of 27.3 months (range, 9.3–100), the median overall survival (OS) was not yet reached and the median event-free survival (EFS) was 72.2 months (range, 5.4–100). The 2-year OS and EFS rates were 76.9% and 62.8%, respectively. No acute graft-versus-host disease (aGVHD) or toxicity-related death occurred in any patient. The median times to platelet and neutrophil recovery were 11.5 days (range, 6–17) and 12.2 days (range, 0–21), respectively. Single-cell RNA sequencing (scRNA-seq) identified enhanced anti-tumor and anti-aging properties of UCB, manifested through activation of immune responses and telomere synthesis/maintenance. These findings suggest that UCB infusion is an effective and safe post-remission adjuvant therapy for elderly AML patients. This study provides evidence that anti-aging therapy may serve as a new and promising dimension in combined cancer treatment.

Tumor microenvironments (TMEs) have received increasing attention in recent years as they play pivotal roles in tumorigenesis, progression, metastases, and resistance to the traditional modalities of cancer therapy like chemotherapy. With the rapid development of nanotechnology, effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed. The appropriate design and fabrication endow nanomedicines with the abilities for active targeting, TMEs-responsiveness, and optimization of physicochemical properties of tumors, thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits. This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments, such as tumor acidosis, hypoxia, and dysregulated metabolism. Finally, this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.