Redox biology represents a universal molecular language that encodes biochemical gradients, distinguishing healthy from diseased tissues with significant precision. The convergence of redox signaling and peptide self-assembly results in a versatile chemical framework for next-generation theranostics. Peptides, programmable, biocompatible, and hierarchically organized, can translate subtle oxidative cues into structural transitions, functional activation, and real-time diagnostic output. Redox-responsive molecular assemblies leveraging disulfide exchange, thiol oxidation, methionine sulfoxidation, and dithiane chemistry enable dynamic assembly, phase transition, or disintegration based on local redox potential. Redox dysregulation, encompassing reactive oxygen species and reactive nitrogen species imbalance, glutathione depletion, and iron-driven lipid peroxidation – governs diverse pathologies from cancer to neurodegeneration. In parallel, beyond traditional delivery platforms, redox-activated phase-separating peptides forming coacervate microdroplets have emerged as versatile drug vectors with high-capacity recruitment of nucleic acids, proteins, and small molecules, with cytosolic release triggered by glutathione. These condensate-like materials exhibit rapid and very high encapsulation efficiency, intracellular uptake, and redox-coded responsiveness. Additionally, imaging probes coupling redox-triggered bond cleavage with optical or magnetic signal activation allow real-time visualization of redox landscapes during therapy. From a translational perspective, progress is accelerated by advances in large-scale solid-phase peptide synthesis, redox-stable manufacturing workflows, and evolving regulatory frameworks. Future redox-responsive peptide coacervates are envisioned as programmable “chemical processors” that sense oxidative flux, interpret biochemical input, and deliver microenvironment-specific outputs. Such adaptive, information-rich architectures position peptide-based redox nanotheranostics as an emerging class of biomaterials capable of combining therapeutic action with the dynamic redox logic of diseases.
The integration of diagnostic imaging and targeted therapy into unified theranostic platforms represents a paradigm shift in precision medicine. Yet, clinical efficacy is often hampered by suboptimal pharmacokinetics that impair target-specific uptake and increase systemic exposure, representing a persistent obstacle to effective in vivo delivery. Bioorthogonal chemistry provides a complementary strategy to address these limitations by enabling high-fidelity chemical reactions to occur directly within the living subject. By facilitating strategies such as in vivo pretargeting and stimulus-responsive payload release, these distinct chemical tools allow for the temporal decoupling of targeting vectors from cytotoxic radioactivity, and ‘click-to-clear’ strategies additionally provide selective clearance of circulating radioconjugates to expand the therapeutic window. This capability for on-demand molecular assembly and activation has broadened the scope of nuclear medicine and stimulated growing interest in bioorthogonal-based interventions. This review summarizes the latest advancements in utilizing bioorthogonal chemistry for theranostics and mainly focuses on pretargeted imaging and therapy approaches as well as bioorthogonal cleavage-mediated activation. In addition, we critically examine the translational barriers and clinical prospects of implementing these advanced chemical systems in patient care.
Chronic wounds continue to pose a major clinical and socioeconomic challenge, affecting millions of patients worldwide. Their persistence is often driven by impaired oxygenation, persistent infection, biofilm formation, and dysregulated inflammation, all of which disrupt the normal healing cascade. In recent years, gas-based therapeutics particularly oxygen (O₂) and nitric oxide (NO) have attracted considerable attention for their multifaceted roles in tissue repair. Oxygen is essential for cellular metabolism, angiogenesis, and collagen deposition, whereas NO modulates vascular tone, coordinates immune responses, and provides potent antimicrobial activity. This review systematically examines the molecular mechanisms by which O₂ and NO individually and synergistically regulate all four phases of wound healing with particular emphasis on the signalling that link oxygen availability to NO biosynthesis. The challenges related to delivery, dosage, and stability persist. Importantly, a growing body of evidence highlights the biochemical interplay between O₂ and NO, where oxygen stabilizes NO synthesis, and NO mediates oxygen signalling pathways, particularly in angiogenesis and immune modulation. This interdependence suggests that combined O₂-NO delivery may offer superior therapeutic outcomes compared to single-gas approaches. Advances in biomaterials, nanotechnology, and smart dressing design now enable the development of dual-delivery systems capable of controlled and sustained release. Future work should focus on personalized wound care strategies, integration of dual gas therapies with conventional modalities, and large-scale clinical validation to translate biology into practice.
For over four decades, poly(ethylene glycol) (PEG) has been the undisputed gold standard for conferring stealth properties to nanomedicines and polymer therapeutics. However, the widespread presence of pre-existing anti-PEG antibodies in the general population, which was intensified by recent mRNA COVID-19 vaccination campaigns, has exposed critical immunological liabilities, including accelerated blood clearance, hypersensitivity reactions and reduced therapeutic efficacy. Poly(2-oxazoline)s, particularly poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-ethyl-2-oxazoline) (PEtOx), have emerged as promising PEG alternatives. Their hydrolytically stable amide backbone, absence of ether oxygens (key recognition motifs for anti-PEG antibodies), tunable hydrophilicity, chemical versatility, tailor-made properties and excellent antifouling characteristics position them as ideal stealth candidates. This review discusses the progress that has been made on poly(2-oxazoline)s as alternatives to PEG by discussing the state-of-the-art in poly(2-oxazoline) stealth/antifouling properties, pharmacokinetics, and immunogenicity, structured by polymer type, namely PMeOx, PEtOx, and other polymers, such as chiral poly(2-oxazoline)s and poly(2-oxazine)s. This review aims to give an overview of the current status, which can be used as starting point for getting acquainted with poly(2-oxazoline)s as PEG-alternatives for those new to the field and as a source of inspiration for future research in the area.
Osteoarthritis (OA) and rheumatoid arthritis (RA) are inflammatory joint disorders that involve overlapping immune-cell populations with distinct etiologies. Key pathological features in the microenvironments of both OA and RA are redox imbalance, and dysregulated immune responses. From the perspective of the pathological microenvironment, a high level of reactive oxygen species (ROS) triggers inflammatory cascades, shifting macrophage polarization to an M1 (pro-inflammatory) phenotype, leading to cartilage erosion and tissue damage. Current therapeutics comprising anti-inflammatory drugs and antioxidant agents provide symptomatic relief, yet possess significant challenges, especially in addressing the interconnected axis (redox-immune axis). Nanozymes, catalytic nanomedicine with their enzyme-mimicking properties such as peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT), alongside with high stability, adjustable catalytic activities and adaptability to specific microenvironment, have emerged as promising platform in arthritis treatment to restore redox homeostasis and immune responses. Moreover, microenvironment-adaptive and combinational nanozyme systems further advance targeted and multimodal therapeutic strategies in arthritis. This review highlights the pathological rationale for nanozymes in OA and RA, and explores nanozyme-immune crosstalk, focusing on redox homeostasis, immune regulation, and microenvironment-sensitive or combinational platforms. Furthermore, safety concerns regarding nanozyme treatment, and future avenues of research are drawn to advance nanozyme-based therapies for arthritis.
