Gaining insight into osmotic pressure and its biological implications is pivotal for revealing mechanisms underlying numerous fundamental biological processes across scales and will contribute to the biomedical and pharmaceutical fields. This review aims to provide an overview of the current understanding, focusing on two central issues: (i) how to determine theoretically osmotic pressure and (ii) how osmotic pressure affects important biological activities. More specifically, we discuss the representative theoretical equations and models for different solutions, emphasizing their applicability and limitations, and summarize the effect of osmotic pressure on lipid phase separation, cell division, and differentiation, focusing on the mechanisms underlying the osmotic pressure dependence of these biological processes. We highlight that new theory of osmotic pressure applicable for all experimentally feasible temperatures and solute concentrations needs to be developed, and further studies regarding the role of osmotic pressure in other biological processes should also be carried out to improve our comprehensive and in-depth understanding. Moreover, we point out the importance and challenges of developing techniques for the in vivo measurement of osmotic pressure.

Nanoparticles (NPs) have been widely applied as drug carriers in drug delivery, due to their unique physical and structural properties. To achieve the drug delivery purpose, receptor-mediated endocytosis is a primary explored mechanism to internalize NPs into tumor cells. During the endocytosis process, properties of NPs, including size, shape, and surface functionality, play an important role in determining the final drug delivery efficacy. Many of these NP properties have been extensively explored individually. However, the multiple NP properties naturally interplay with each other in the endocytosis process to determine the internalization efficiency together. Therefore, it is significantly important to understand the interplay of different NP properties to improve the NP’s final delivery efficacy. In this review, we focus on the interplay of NPs properties on the endocytosis process to summarize the relevant experimental observations and physical mechanisms. Particularly, three different aspects are discussed in detail, including the interplay between size and shape; size and elasticity; shape and elasticity. We have summarized the most recent works and highlighted that building up systematic understandings for the complex interplay between NP properties can greatly help a better design of NP platforms for drug delivery.

Epithelial cell adhesion molecule (EpCAM), a tumor antigen for antibody–drug conjugates (ADCs), is highly expressed in many epithelial cancers. However, the clinical progress of EpCAM ADCs has been challenging, primarily due to their toxicity in normal high-expression tissues such as the gastrointestinal tract. CLDN3 is highly co-expressed with EpCAM in various human malignancies, coupled with its minimal presence in normal tissues, rendering it an ideal target for developing potent therapeutic ADCs. Here, we developed a bispecific ADC (BsADC) targeting EpCAM and CLDN3, designed to avoid toxicity in normal tissues with high EpCAM expression. The parental monoclonal antibodies (mAbs) were screened for high binding and endocytosis activities on tumor cell lines. We then modified them into monovalent structures and selected clones with decreased binding and endocytosis activities. We combined these clones into bispecific antibodies (BsAbs) and finally chose the molecules with restored binding and endocytosis activities as lead molecules. The BsADCs were generated by conjugating the Drutecan (Dxd) to BsAbs via a cleavable linker. These conjugates exhibit potent binding and effectively inhibit the growth of tumor cells with high levels of both EpCAM and CLDN3, indicating their anti-tumor efficacy. Importantly, they show weak binding to cells with high EpCAM but low CLDN3, implying minimal toxicity to normal tissues with elevated EpCAM expression. Moreover, the BsADCs displayed advantageous pharmacokinetics and low toxicity in mice. These findings position the BsADCs targeting EpCAM and CLDN3 as promising candidates for treating multiple solid tumors.

Gaining insight into the in situ receptor–ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and will contribute to drug discovery and biomedical application. An important issue involved is how the receptor–ligand binding responds to mechanical stimuli. This review aims to provide an overview of the current understanding of the effect of several representative mechanical factors, such as tension, shear stress, stretch, compression, and substrate stiffness on receptor–ligand binding, wherein the biomedical implications are focused. In addition, we highlight the importance of synergistic development of experimental and computational methods for fully understanding the in situ receptor–ligand binding, and further studies should focus on the coupling effects of these mechanical factors.

Cell-cell communication is crucial for cells to sense, respond and adapt to environmental cues and stimuli. The intercellular communication process, which involves multiple length scales, is mediated by the specific binding of membrane-anchored receptors and ligands. Gaining insight into two-dimensional receptor-ligand binding kinetics is of great significance for understanding numerous physiological and pathological processes, and stimulating new strategies in drug design and discovery. To this end, extensive studies have been performed to illuminate the underlying mechanisms that control intercellular receptor-ligand binding kinetics via experiment, theoretical analysis and numerical simulation. It has been well established that the cellular microenvironment where the receptor-ligand interaction occurs plays a vital role. In this review, we focus on the advances regarding the regulatory effects of three factors including 1) protein-membrane interaction, 2) biomechanical force, and 3) bioelectric microenvironment to summarize the relevant experimental observations, underlying mechanisms, as well as their biomedical significances and applications. Meanwhile, we introduce modeling methods together with experiment technologies developed for dealing with issues at different scales. We also outline future directions to advance the field and highlight that building up systematic understandings for the coupling effects of these regulatory factors can greatly help pharmaceutical development.

Mechanical microenvironment and cellular senescence of trabecular meshwork cells (TMCs) are suspected to play a vital role in primary open-angle glaucoma pathogenesis. However, central questions remain about the effect of shear stress on TMCs and how aging affects this process. We have investigated the effect of shear stress on the biomechanical properties and extracellular matrix regulation of normal and senescent TMCs. We found a more significant promotion of Fctin formation, a more obvious realignment of F-actin fibers, and a more remarkable increase in the stiffness of normal cells in response to the shear stress, in comparison with that of senescent cells. Further, as compared to normal cells, senescent cells show a reduced extracellular matrix turnover after shear stress stimulation, which might be attributed to the different phosphorylation levels of the extracellular signal-regulated kinase. Our results suggest that TMCs are able to sense and respond to the shear stress and cellular senescence undermines the mechanobiological response, which may lead to progressive failure of cellular TM function with age.