Biologic therapies for diabetes have advanced significantly through molecular engineering strategies that optimize therapeutic stability, pharmacokinetics, and delivery. This review presents an integrated overview of design principles used to develop insulin, glucagon, amylin analogs, and GLP-1 receptor agonists, highlighting their unique physicochemical challenges and therapeutic requirements. Structural modifications-including amino acid substitutions, peptide stapling, glycosylation, and PEGylation-are discussed for their roles in enhancing stability, reducing aggregation, and extending half-life. Strategies for tuning pharmacokinetics are examined, ranging from sequence-driven solubility modulation to formulation-based depot formation and vascular binding mechanisms. Various administration routes, including oral, inhaled, and intranasal delivery, are evaluated for their potential to improve adherence and more closely mimic endogenous hormone profiles. The review also addresses the development of combination therapies and multi-receptor agonists designed to synergize complementary hormonal pathways. Finally, recent progress in glucose-responsive systems is reviewed, emphasizing molecular and materials-based approaches that enable real-time, glucose-triggered therapeutic activation. Taken together, the evolution of diabetes therapeutics exemplifies the application of core molecular design concepts in biologic drug development. The strategies outlined herein not only address the complex demands of glycemic control but also provide a broadly applicable framework for engineering next-generation protein-based therapies for applications beyond diabetes.

Rising Star: Rewriting the Code of Life for the Future of Food.

Cation-π interactions at the Cu-HHTP/MXene hybrid interface for efficient electrocatalytic CO2 reduction.

Strategic molecular engineering of ultrastable porous organic polymer engineered with tetraethynylpyrene-functionalized benzoxazine for superior CO2 capture via solid-state chemical conversion

Molecular engineering of a Rigid-Flexible phosphorus Macromolecule for Transparent, Mechanically Reinforced, and Flame-Retardant epoxy resins

From biomolecules to a stable zinc Interface: Green molecular engineering for high-performance, durable zinc-air batteries

Molecular engineering of Co ion–imprinted sites on metal–organic frameworks and facile photodeposition for the selective recovery and upcycling of Co(II)

Molecular engineering strategies for high-performance polyamide nanofiltration membranes: A review

Binder molecular engineering regulates the interface of solid electrolytes

The immune system employs molecular switches to maintain dynamic homeostasis, yet malignant cells often learn from these natural switches and ultimately evade immune surveillance, leading to immune tolerance and tumor deterioration. Chemically synthetic switches designed to redirect immune signaling pathways are highly desired for reversing this pathological trajectory but are rarely reported. Herein, we develop a synthetic DNA framework (DF) switch that reprograms macrophage-mediated immune clearance of Programmed Cell Death-Ligand 1 Positive (PD-L1+) extracellular vesicles (EVs) in vivo. This synthetic switch is composed of a ligand (Man6)-terminated PD-L1-targeting aptamer (MJ5C) and a DF, termed hereinafter as MJ5C-Man6-DF, which operates through a recognition-then-recruitment mechanism. Thus, in the "off state", MJ5C stably resides within the DF, retaining Man6 in its inner cavity. However, upon target recognition, MJ5C switches to the "on state" and binds to PD-L1+ EVs, conferring conformational changes that allow coating of its terminal Man6 on EVs. Man6-coated EVs then recruit macrophages via the membrane receptor CD206, enabling efficient phagocytosis. MJ5C-Man6-DFs were shown to perform with exceptional stability and specificity, augmenting αPD-L1 therapy by 90.7% while boosting T cell activation by 55% in vivo. Therefore, our aptamer-driven DF switch provides a strategy for precise immune reprogramming in the field of DNA-based molecular engineering.

Stretchable organic electrochemical transistors (S-OECTs) are known for their high transconductance, low operating voltage, and excellent mechanical compliance. Despite advancements in molecular design and geometric engineering, achieving both high transconductance and stable performance under a large strain remains a challenge. This study demonstrates high-transconductance intrinsically stretchable vertical OECTs, fabricated via a smooth stretchable bilayer electrode and a stretchable organic semiconductor. The combination of a smooth evaporated Au layer and transfer printing of Ag NWs endows the electrode with sub-nanometer surface roughness and high conductivity under stretching, ensuring the devices with both high transconductance (∼55 mS) and stretchability (100%). Under 100% strain, the devices successfully demonstrate rich synaptic functionalities and achieve a remarkably high paired-pulse facilitation (PPF) index of 319.82%. When configured into a reservoir computing network, the system achieves 91.76% accuracy in handwritten digit recognition under 100% strain, showcasing significant potential for wearable neuromorphic electronics applications.

Molecular engineering has played a pivotal role in biomedical fields, driving significant advancements in gene therapy, disease diagnosis, and biosensing. However, nucleic acid molecular engineering faces various challenges including vast design spaces, complex structure-function relationships, lengthy application validation cycles, and inefficient optimization processes. Machine learning (ML), with its superior pattern recognition, multidimensional data integration, and automated optimization capabilities, offers a unique opportunity to construct predictive models of sequence-structure-function relationships, thereby enabling a paradigm shift from empirically driven to data-driven approaches. This review systematically surveys recent progress in ML applications across three major domains: nucleic acid structure construction, performance modulation, and application expansion. It also explores core challenges such as data quality, model interpretability, and experimental validation efficiency, along with potential resolution strategies. These insights are poised to propel nucleic acid molecular engineering from static structure prediction toward dynamic behavior simulation, and from single-molecule design to complex system engineering, guiding future directions in hybrid ML-quantum models and expanded applications to non-canonical nucleic acids for transformative innovation in biomedicine, environmental monitoring, and information technology.

Wrinkles, a prevalent form of line defect in monolayer (1L) 2D materials, significantly degrade their optoelectronic performance by inducing local strain, energy puddles, and charge trapping. This study introduces a wrinkle-selective strategy utilizing trioctylphosphine selenide (TOPSe), which exploits its steric hindrance and electron-donating nature to selectively heal selenium vacancies at strained wrinkle sites in 1L-WSe2. Comprehensive spectroscopic characterization-comprising Raman spectroscopy, photoluminescence spectroscopy, and femtosecond transient absorption microscopy-demonstrated substantial reductions in the defect density, suppressed non-radiative recombination, and prolonged exciton lifetimes. Kelvin probe force microscopy further revealed wrinkle-specific electron doping and spatial homogenization of the conduction band. Field-effect transistors based on TOPSe-treated 1L-WSe2 exhibited more than a two-fold increase in current and mobility, in conjunction with a transition from p-type to n-type conduction. Our findings indicate that wrinkle-targeted molecular engineering is a versatile approach for addressing intrinsic inhomogeneities in 2D materials and enabling high-performance optoelectronic devices.

The replacement of aromatic rings with saturated molecular frameworks is a recent development encapsulated by the motto "escape from flatland" and conceptualized through the use of saturated benzene bioisosteres. This Review summarizes the application of the smallest bicyclic and spirocyclic ring systems as saturated scaffolds, focusing on applications in constructing bioactive molecules. We discuss considerations of their molecular strains, their potential to serve as saturated benzene isosteres in terms of both volume and geometry, and structural data derived from small-molecule and protein crystallography. Additionally, we present general approaches to synthesis, examine the current commercial availability of functional building blocks, and present existing examples of applications of bicyclic systems in drug discovery programs. At least eight structures based on the smallest skeletons have advanced to clinical trials, with one, vanzacaftor, recently receiving U.S. FDA approval. Our analysis indicates that small bicyclic fragments are represented exceptionally unevenly. While bicyclo[1.1.1]pentane and spiro[3.3]heptane have become routine and indispensable in medicinal chemistry over the past decade, ladderane and housane remain exotic and unexplored. We highlight knowledge gaps, aiming to stimulate interest in small saturated skeletons for innovative molecular engineering.

The deployment of high-voltage cathodes for lithium metal batteries (LMBs) imposes stricter requirements on the electrolyte stability. Deep eutectic electrolyte (DEE) is one of the most promising candidates. In DEEs, the strong interaction between the hydrogen bond donor (HBD) and Li+ causes sluggish desolvation, and HBD-anion coordination structure induces severe oxidation decomposition. In this work, electron-withdrawing groups were introduced onto benzonitrile to synergistically tune multiple coordination interactions. Leveraging the stronger electron-withdrawing and steric hindrance effects of trifluoromethyl (-CF3) group, the optimized HBD, 4-Fluoro-2-(trifluoromethyl)benzonitrile (FTFBN), exhibits weaker coordination ability with Li+ and a low HBD-anion coordination number. It constructs an anion-dominated solvation structure and inorganic-rich cathode-electrolyte interphase (CEI) on lithium cobalt oxide (LCO), effectively suppressesing irreversible phase transitions and interfacial side reactions. As a result, the FTFBN-based DEE demonstrates a high Li+ transference number (tLi +) of 0.74 and stable symmetric cell cycling for over 900 h (0.5 mA cm-2 and 0.5 mAh cm-2). Moreover, it supports long-term cycling stability in 4.5V Li‖LCO cells, retaining 84% capacity after 400 cycles. This work highlights the vital role of HBD molecular engineering in optimizing the solvation structure and interfacial chemistry forLMBs.

Sequestration of radiotoxic 226Ra2+ is challenged by its complex coordination chemistry, which requires a precise molecular recognition strategy. Here, we report a supramolecular trap engineered within a stable zirconium metal-organic framework (ZJU-X102-SO4) by integrating a size-selective 24-crown-8 ether with a proximal sulfate anchor. The formation of this preorganized trap and its cooperative binding mechanism were elucidated by single-crystal X-ray diffraction, solid-state NMR, XAFS, and DFT calculations. This dual-recognition design was first validated with the Ba2+ surrogate, affording rapid kinetics (equilibrium in 30 s) and a high capacity (455 mg g-1). For the target 226Ra2+, ZJU-X102-SO4 could remove 70% of 226Ra2+ within 10 min (C0 = 10 Bq mL-1) and demonstrate a capacity of 3.3 × 104 Bq g-1. In high-salinity media, a salting-out effect was observed and ZJU-X102-SO4 showed a high distribution coefficient of 5.3 × 104 mL g-1. The sequestration of 226Ra2+ was also effective in 3 M HNO3. This work presents a molecular engineering strategy for designing sorbents for the targeted sequestration of specific cations from aqueous media.

Organic afterglow probes activated by X-rays hold considerable potential for deep-tissue imaging and cancer therapy. However, their applications are often limited by short-wavelength emission and the inefficient X-ray-induced generation of reactive oxygen species (ROS). To overcome these challenges, we developed a molecularly engineered small-molecule probe that integrates deep-tissue imaging through X-ray-triggered afterglow (AGL) in the second near-infrared (NIR-II) window. This system features a chemiexcitable phenoxy-adamantylidene donor linked to a rhodamine-based perchlorate acceptor via a vinyl bridge, forming a conjugated donor-π-acceptor (D-π-A) architecture. The extended π-conjugation and reduced excited-state energy of this framework enable efficient NIR-II emission (up to ∼1100 nm). Upon X-ray irradiation, the generated singlet oxygen (1O2) adds to the adamantylidene unit, and the resulting chemiexcitation transfers the released energy to the rhodamine perchlorate acceptor to produce an NIR-II afterglow. Meanwhile, the probe enables sustained singlet-oxygen production, synergistically enhancing tumor cell eradication while reducing the required radiation dose. This integrated molecular design establishes a unified platform for NIR-II afterglow-guided radiotheranostics, demonstrating the potential of rational molecular engineering to address the limitations of conventional X-ray-responsive agents and achieve spatiotemporally controlled cancer diagnosis and treatment.

Advances in enzymatic O-glycosylation of flavonoids: Strategies for control of regioselectivity and enhancement of efficiency.

The growing demand for sustainable, biocompatible, and multifunctional sensing materials has intensified interest in melanin and its derivatives, including melanin-inspired polymers and composites. Melanin is a naturally occurring biopolymer whose intricate structure and diverse chemical composition give rise to a remarkable combination of optical, electrical, and chemical properties. Key physicochemical characteristics, such as broadband optical absorption, hydration-dependent conductivity, redox activity, and metal ion coordination, are closely linked to melanin’s signal transduction capabilities and underpin its relevance in sensing applications. Recent advances in melanin-based sensing technologies encompass pH, humidity, chemical, biological, and optical platforms, with particular emphasis on hybrid systems incorporating graphene, silicon, or nanomaterials, and printable or wearable device architectures. These developments have enabled enhanced performance and broadened potential application fields. However, persistent challenges, including intrinsic heterogeneity, limited selectivity, relatively low electrical conductivity, and poor long-term operational stability, still limit practical implementation. Emerging molecular engineering and advanced fabrication strategies are being developed to address these limitations. Together, these findings position melanin as a versatile, eco-compatible, and functionally rich material, with a significant potential to underpin the next generation of sustainable sensing technologies.

Comprehensive Summary Dibenzylidene ketone (DBK) photoinitiators (PIs) hold promise for one‐photon polymerization (OPP) and two‐photon lithography (TPL), owing to easily synthesized extended π‐conjugated frameworks via one‐step aldol condensation. However, industrial adoption is limited by poor solubility and critical OPP reactivity/TPL processability mismatch. Herein, we report a dual‐parameter molecular engineering strategy for tert ‐butylcarbazole‐functionalized DBK PIs, tuning N ‐alkyl chains (methyl, ethyl, n ‐butyl, n ‐dodecyl) and cyclic ketone spacers (C5: cyclopentanone; C6: cyclohexanone) to optimize polymerization properties. For OPP, C5‐DBKs exhibit enhanced visible photosensitivity, enabling rapid kinetics under 405–520 nm LEDs; N ‐dodecyl derivatives show excellent photobleaching and deep curing. For TPL, C5‐DBKs have superior two‐photon absorption ( σ TPA ) but C6‐DBKs offer better solubility (1 wt% in PETA) and act as efficient one‐component TPL PIs. Using a 780 nm fs laser, N1C6/PETA enables high‐precision fabrication: threshold matrix writing exhibits wide processing window and good uniformity, achieving sub‐200 nm resolution (167 nm linewidth at 45 mW, 50 mm·s –1 ) and high‐fidelity microlens arrays. Complex 3D microstructures (intricate logos, sub‐micron text, Chinese jade belt bridge, nanoscale‐pore photonic crystals) demonstrate versatility in photonics, metamaterials and micro‐pattern anti‐counterfeiting. This work establishes OPP/TPL structure‐activity relationships (SARs) and a versatile molecular design platform for industrial coatings and micro/nano‐manufacturing.