On-demand engineering of cell membrane receptors to nongenetically intervene in cellular behaviors is still a challenge. Herein, a membraneless enzyme biofuel cell-based self-powered biosensor (EBFC-SPB) was developed for autonomously and precisely releasing Zn2+ to initiate DNAzyme-based reprogramming of cell membrane receptors, which further mediates signal transduction to regulate cellular behaviors. The critical component of EBFC-SPB is a hydrogel film on a biocathode which is prepared using a Fe3+-cross-linked alginate hydrogel film loaded with Zn2+ ions. In the working mode in the presence of glucose/O2, the hydrogel is decomposed due to the reduction of Fe3+ to Fe2+, accompanied by rapid release of Zn2+ to specifically activate a Zn2+-responsive DNAzyme nanodevice on the cell surface, leading to the dimerization of homologous or nonhomologous receptors to promote or inhibit cell proliferation and migration. This EBFC-SPB platform provides a powerful \"sensing-actuating-treating\" tool for chemically regulating cellular behaviors, which holds great promise in precision biomedicine.

Acetylation is an important approach to improve the bioactivity of polysaccharides; however, the mechanisms have not been fully understood. As a key component of longan for exerting health promoting function, longan polysaccharide was hypothesized may achieve elevated immunoregulatory activity after acetylation. A bioactive longan polysaccharide (LP) composed of (1 → 6)-α-d-glucan (84.1 %) and with an average Mw of 9.68 × 104 kDa was acetylated to different degree of substitutions (DS) in this study. Key structural changes responsible for improvement in immunoregulatory activity were identified, and underlying mechanisms were investigated. Acetylated LP (Ac-LP) with DS 0.37, 0.78 and 0.92 were obtained. Structural characterization identified the substitution of acetyl groups occurs at O-6 positions of t-Glc non-selectively, while the backbone structure was not apparently changed. This resulted in increased expression of cytokines (IL-10, IL-6 and TNF-α) and ROS production in RAW264.7 macrophages, indicating improved immune activity which is positively related to the DS of Ac-LP. This is attribute to additional cellular receptors for Ac-LP (CD14 and Dectin-1) apart from receptors for LP (TLR4 and Ca2+ receptors), as well as the relative higher protein expression of TLR4-MyD88 signaling pathways. These results would provide guidance for the utilization of acetylated polysaccharides with improved immunoactivity.

Specific interactions between ligands and receptors on cell surface play an important role in the cell biological process. Nucleic acid aptamers as commonly used ligands enable specific recognition and tight binding to membrane protein receptors for modulation of cell fate. Therefore, molecular probes with aptamers can be applied for cancer diagnosis and targeted therapy by targeting overexpression membrane proteins of cancer cells. However, because of their fast degradation and rapid glomerulus clearance in vivo, the applications of aptamers in physiological conditions remain challenged. Inspired by natural multivalent interactions, many approaches have been developed to construct multivalent aptamers to improve the performance of aptamers in complex matrices with higher binding affinity, more stability, and longer circulation time. In this review, we first introduce the aptamer generation from purified protein-based SELEX and whole cell-based SELEX for targeting the cell surface. We then highlight the approaches to fabricate multivalent aptamers and discuss their properties. By integrating different materials (including inorganic nanomaterials, diacyllipid, polymeric nanoparticles, and DNA nanostructures) as scaffolds with an interface modification technique, we have summarized four kinds of multivalent aptamers. After that, representative applications in biosensing and targeted therapy are illustrated to show the elevated performance of multivalent aptamers. In addition, we analyze the challenges and opportunities for the clinical practices of multivalent aptamers.

Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs.