Most membrane-less organelles (MLOs) formed by LLPS contain both nucleic acids and IDR-rich proteins. Currently while IDRs are well-recognized to drive LLPS, nucleic acids are thought to exert non-specific electrostatic/salt effects. TDP-43 functions by binding RNA/ssDNA and its LLPS was characterized without nucleic acids to be driven mainly by PLD-oligomerization, which may further transit into aggregation characteristic of various neurodegenerative diseases. Here by NMR, we discovered unexpectedly for TDP-43 PLD: 1) ssDNAs drive and then dissolve LLPS by multivalently and specifically binding Arg/Lys. 2) LLPS is driven by nucleic-acid-binding coupled with PLD-oligomerization. 3) ATP and nucleic acids universally interplay in modulating LLPS by competing for binding Arg/Lys. However, the unique hydrophobic region within PLD renders LLPS to exaggerate into aggregation. The study not only unveils the first residue-resolution mechanism of the nucleic-acid-driven LLPS of TDP-43 PLD, but also decodes a general principle that not just TDP-43 PLD, all Arg/Lys-containing IDRs are cryptic nucleic-acid-binding domains that may phase separate upon binding nucleic acids. Strikingly, ATP shares a common mechanism with nucleic acids in binding IDRs, thus emerging as a universal mediator for interactions between IDRs and nucleic acids, which may underlie previously-unrecognized roles of ATP at mM in physiology and pathology.

Condensate‐modifying therapeutics (c‐mods), comprising low–molecular‐weight compounds (~1.5 kDa) and related agents such as RNAs and metabolites like ATP, are emerging as promising drug candidates for neurodegenerative disorders, cancer, and viral infections. These compounds modulate liquid–liquid phase separation (LLPS), a biophysical process driven by intrinsically disordered regions, low‐complexity domains, and multivalent non‐covalent interactions (hydrogen bonds, van der Waals forces, hydrophobic, and electrostatic interactions). LLPS governs the formation of biomolecular condensates essential for gene regulation, signaling, stress responses, and cellular organization. By selectively inhibiting or promoting condensation, we show that c‐mods offer strategies to manage diseases presented with aberrant phase separation. Mechanistic insights into LLPS dynamics provided by specific physicochemical features (planar structures and polarity) of c‐mods open avenues for accelerating drug discovery, repurposing, and synergistic therapies. We highlight scaffolds, charged molecules, and ions that modulate LLPS. We integrate recent advances in understanding the roles of c‐mods in regulating viral protein assemblies; however, the function of LLPS and its regulation in other microorganisms remains underexplored. Future directions include engineering peptide‐based therapeutics, designing artificial condensates, and employing AI‐driven target identification to discover novel LLPS‐associated drug targets. Additionally, biomaterials and industry‐led initiatives in condensate‐targeted drug discovery are broadening therapeutic intervention across diverse diseases.

Melatonin (MT), as a hormone regulating the rhythm of sleep, is widely used in health products. However, illicit and excessive use of MT might cause undesirable effects. Therefore, it is essential to establish highly sensitive and specific rapid methods for MT analysis in health products. In this study, we established indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and indirect competitive chemiluminescent enzyme immunoassay (ic-CLEIA) for sensitive and selective detection of MT in health products. Under optimal conditions, half-maximum inhibitory concentration (IC₅₀ value) and limit of detection (LOD, IC₁₀ value) for MT by ic-ELISA were 0.25 ng mL⁻¹ and 0.03 ng mL⁻¹ respectively, while the IC₅₀ and LOD of ic-CLEIA were lower at 0.17 ng mL⁻¹ and 0.03 ng mL⁻¹ respectively. Three MT-free Chinese patent medicines were spiked with MT and the recovery rates ranged from 71.89% to 117% (ic-ELISA) and 83.66% to 107.17% (ic-CLEIA). The level of MT in six MT-containing health products was assessed in parallel using the developed methods and HPLC. Both ic-ELISA and ic-CLEIA showed good consistencies (R² = 0.999 and 0.993, respectively) with HPLC, indicating that the two methods developed were sensitive, fast, and reliable for application in MT analysis.

Infections caused by antibiotic-resistant Escherichia coli are a threat to human and animal health globally. Phage therapy has made great progress for the treatment of drug-resistant infections, but it is still unclear whether E. coli resistance to antibiotics could change the lysis ability of phages. In this study, we demonstrate that over expression of AmpC, an important β-lactamase for ampicillin resistance, promotes lysis of E. coli by phage utilizing OmpA as a receptor. E. coli strains expressing more AmpC showed higher levels of OmpA, an E. coli outer membrane protein known to serve as a receptor for T-even phages, which resulted in increased adsorption and lysis by the phage tested in this study. These data demonstrate that increased ampicillin resistance can increase the sensitivity of E. coli to some lytic phage, which provides evidence for the feasibility of synergistic application of phage and antibiotics.