With deep-learning-powered advances in protein design methods, there is an ongoing paradigm shift in protein engineering from random selection to intentional computational design methods. Here we describe the current state of de novo protein design. While there is still room for improvement in success rates and activities, the long-standing challenges of designing new protein structures, assemblies and protein binders are close to being solved. The key current questions in these areas are not how to design, but what to design, and open-source design methodology such as RFdiffusion and ProteinMPNN together with protein structure prediction tools enable biochemists and molecular biologists to broadly explore possible applications. There has also been considerable progress in the de novo design of small-molecule target binders, enzymes and multistate protein systems. Current challenges for methods development include design of catalysts for reactions with high energy barriers and, more generally, design of switches and nanomachines that integrate binding, conformational change and catalysis. Over the next five to ten years, we anticipate the design of sophisticated protein nanomachines and materials with functionality ranging far beyond that generated during natural evolution for a wide range of applications in medicine, technology and sustainability.
Radiopharmaceuticals have long demonstrated precise, organ- and receptor-specific targeting in humans, supported by well-characterized pharmacokinetics, standardized formulation, and regulatory validation; however, the carrier systems underlying these agents remain largely underexplored as platforms for therapeutic delivery. This review introduces a translational framework that repositions clinically validated radiopharmaceutical carriers, including peptides, nanocolloids, lipophilic complexes, and antibody fragments, as ready-to-deploy scaffolds for targeted drug delivery and theranostic applications. Integrating classical radiopharmaceutical principles with advances from 2018 to 2025, this work examines how established systems based on technetium-99m (99ᵐTc), gallium, lutetium, rhenium, copper, iodine, and actinium can be systematically re-engineered through linker design, bifunctional chelation, and payload integration. Unlike conventional nanocarriers that rely heavily on preclinical optimization and passive targeting mechanisms, these platforms offer pre-validated human biodistribution, reproducible pharmacokinetics, and compatibility with good manufacturing practice (GMP), providing a distinct advantage for clinical translation. Emerging clinical evidence, including peptide-drug conjugates and antibody-based systems, highlights both the feasibility and current limitations of this approach, particularly the gap between diagnostic success and therapeutic adaptation. By integrating mechanistic insights, design strategies, and translational considerations, this review proposes a shift from de novo carrier design toward the strategic repurposing of clinically proven systems, with the potential to reduce translational attrition and accelerate the development of precision therapeutics and next-generation theranostic platforms.
Alzheimer's disease (AD) represents a pressing challenge in modern medicine, with current therapeutics offering only symptomatic relief. Peptide-based therapeutics have emerged as promising candidates owing to their target specificity, favorable safety profiles, and ability to modulate protein-protein interactions inaccessible to small molecules. This narrative review evaluates medicinal chemistry and artificial intelligence (AI)-driven approaches that are reshaping peptide drug discovery for AD, spanning target selection, sequence design, synthesis optimization, and central nervous system (CNS) delivery. Peptides targeting key AD pathological mechanisms-including amyloid-β (Aβ) aggregation inhibition, tau hyperphosphorylation disruption, and neurotrophic signaling enhancement-are discussed alongside strategies such as cyclization, D-amino acid incorporation, PEGylation, and peptidomimetic design to improve metabolic stability and blood-brain barrier (BBB) penetration. We review automated fast-flow peptide synthesis with inline UV-vis monitoring as a platform for rapid, high-fidelity preparation of complex sequences suitable for translational development. Delivery platforms-including cell-penetrating peptides, intranasal formulations, and nanocarrier systems-which primarily increase systemic exposure or fundamentally alter CNS distribution mechanisms are presented. AI and machine-learning (ML) technologies, molecular simulations, and structure-prediction systems are examined as an integrated pipeline that supports end-to-end design, validation, and optimization, with emphasis on rigorous QSAR and docking/MD validation practices. Clinical translation is analyzed through peptide repurposing (e.g. GLP‑1 receptor agonists, intranasal insulin, oxytocin), dedicated peptide candidates, and evolving regulatory expectations. Finally, we outline concrete design checklists for CNS ready peptides, discuss key translational bottlenecks, and propose priorities for the next 5-10 years of peptide-based AD therapy development.
Many therapeutically relevant membrane proteins possess druggable sites at the lipid-protein interface, but principles guiding ligand design for these sites are not well-defined. CFTR potentiators, a clinically validated drug class for cystic fibrosis, offer a compelling model for exploring membrane-targeted design principles, as their efficacy depends on sustained intramembrane binding to prolong channel opening and chloride conductance. Here, we systematically modified the lipophilic substituent of the CFTR potentiator ABBV-974 and identified an analog that confers markedly increased functional residence time, as measured by delayed current decay after compound washout in patch-clamp assays. Kinetic analysis incorporating the physicochemical properties of the lipophilic substituents suggests that this increased kinetic stability may arise from an increased residence time in the cell membrane, consistent with qualitative results of molecular dynamics simulations. These results establish a structure-function link between membrane-facing ligand modifications and functional target engagement and potentially offer generalizable strategies for designing probe molecules and drugs that stably engage lipid-exposed binding sites on membrane proteins.
The development of new advanced functional materials from low-molecular-weight gelators and their new potential applications have occupied a considerable place in research. The present study involves the design of dipeptide-based organogelators with enhanced hydrogen bonding network potentials and phase-selective capacities, possessing a minimum gelation concentration of 0.2-0.4% w/v in different fluids. Seven new dipeptide organogelators were prepared based on a one-step reaction from two-component salt forms, the combination of Nε-alkanoyl-L-lysine ethyl ester with N-alkanoyl-L-amino acids (L-alanine, L-leucine, and L-phenylalanine), with high yields of up to 90. All the gel materials were extremely stable at room temperature, having a shelf life of several months, and formed gels in pharmaceutical fluids such as ethyl palmitate, ethyl myristate, and ethyl laurate, 1,2-propanediol, and liquid paraffin (oils widely used in pharmaceutical formulations), which meet the criteria of biological materials delivery. Their gelation properties were evaluated by rheological measurements. A very significant breakthrough in the current study is that organogels remove the toxic dye, crystal violet (CV), from water in a phase-selective manner with an extremely low gelator concentration. The dye and gelators are successively recovered via ethanol precipitation after the completion of the phase extraction process. Molecular dynamic calculations provide evidence for the 3D structures of the gels.
The current work aims to fabricate and examine a delafloxacin (DFX)-loaded ethosomal (ETHs) gel for improved topical delivery and improved antibacterial efficiency against skin infections. ETHs were prepared using the cold method followed by two-stage homogenization, involving vesicle fabrication and subsequent gel conversion. A Quality by Design framework was employed, with initial screening using a fractional factorial design and optimization through a Box-Behnken design. Entrapment efficiency (EnE), Vesicle size, and PDI were chosen as critical quality attributes. The optimized nanoformulation was evaluated for size, morphology, drug release, cytotoxicity, irritation potential, ex vivo studies antimicrobial activity, and skin safety. The optimized DFX-ETHs exhibited a vesicle size of 263.6 ± 3 nm, zeta potential of - 5.99 ± 1.466 mV, PDI of 0.173 ± 0.019, and EnE of 90.17 ± 0.14%. FE-SEM confirmed globular vesicles with a smooth surface. The formulation showed sustained drug release following Weibull kinetics. Cytotoxicity studies on NIH/3T3 cells and irritation studies using HET-CAM and rat skin models confirmed the cytocompatible and non-irritant nature of the formulation. Enhanced antimicrobial activity against Staphylococcus aureus and Cutibacterium acnes was observed compared to DFX dispersion. The ex vivo studies results showed that the ETHs formulation significantly improved drug permeation relative to the free DFX. The results demonstrate that ethosomal gel systems are a potential and safe carrier for the topical application of DFX, offering improved antibacterial efficacy against bacterial skin infections.
The incidence of central nervous system (CNS) disorders is increasing worldwide, while the development of CNS drugs remains extremely challenging due to high costs, long development cycles, and high failure rates. The CNS is highly protected by physiological barriers, particularly the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), which severely restrict the entry of most therapeutic agents. Self-assembled nanocarriers (SA-NCs), characterized by relatively simple component composition and straightforward preparation processes, can be rationally engineered to bypass or penetrate these barriers, thereby enabling controlled and targeted drug delivery to the CNS. This review systematically summarizes recent advances in self-assembled nanoplatforms for CNS therapy. It first introduces the anatomical and functional barriers of the CNS along with current routes of administration. Subsequently, it explains the basic design principles and mechanisms of molecular self-assembly (SA), highlighting its unique advantages. The review then examines the multifunctional strategies of SA-NCs from the perspective of a spatiotemporal delivery process. Particular emphasis is placed on their ability to cross the BBB through membrane-translocating modifications for enhanced penetration, and subsequently accumulate at disease sites via functional modifications for targeted therapy. Finally, we discuss recent therapeutic applications in various CNS disorders and provide critical insights into current challenges in clinical translation, offering guidance for the future development of self-assembled nanomedicines.
The drug development for central nervous system (CNS) disorders, particularly neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, faces formidable challenges. While proteolysis-targeting chimeras (PROTACs) represent a paradigm-shifting modality by redefining target engagement mechanisms, their clinical translation remains hindered by limited blood-brain barrier (BBB) permeability and suboptimal pharmacokinetic profiles. In recent years, a range of CNS-targeted delivery strategies have emerged, advancing PROTAC research toward more translatable therapeutic applications. This review highlights recent advances and persistent challenges in noninvasive BBB-penetrant delivery systems, including viral vectors, engineered exosomes, functionalized nanocarriers, and cell membrane-derived biomimetic vehicles, with a particular emphasis on intranasal administration as a direct route to the brain. Parallel progress in rational molecular engineering, encompassing E3 ligase selection, linker polarity and rigidity modulation, and optimization of target-binding ligands, has further enhanced PROTAC drug-likeness and BBB transport efficiency. Current CNS-directed PROTAC designs increasingly incorporate cell-penetrating peptides, nanoparticles, and prodrug formulations to balance stability, selectivity, and brain exposure. Future advanced PROTAC delivery platforms require integrating multifunctional nanocarriers with rational structural optimization to enhance BBB permeability. Further artificial intelligence-accelerated molecular design and targeted protein degradation technologies offer novel avenues for addressing undruggable CNS targets.
Afterglow imaging shows distinct advantages for bioimaging, such as significantly reduced background signals, an enhanced signal-to-background ratio, and excitation-free in situ detection. To achieve real-time molecular visualization and improve diagnostic specificity, various activatable afterglow probes have been developed that selectively respond to biological targets or microenvironmental stimuli. This Review systematically summarizes organic activatable afterglow probes. We introduce their main material categories and luminescence mechanisms, and analyze chemical design strategies for constructing responsive afterglow probes, including target-cleavable linkers, conformational switching, and energy transfer regulation. We also discuss strategies to optimize imaging performance, such as extending emission lifetime, red-shifting emission to tissue-transparent windows, improving luminescence brightness, and using alternative excitation modes (e.g., X-ray or ultrasound) to overcome optical penetration limitations. Representative applications of activatable afterglow nanoprobes are highlighted, covering analyte sensing, lymph node mapping, immune cell imaging, tumor detection, inflammation imaging, and image-guided therapy. Finally, we address current challenges including oxygen dependence, biocompatibility, unified evaluation standards, and scalability, and propose future directions to promote the translation of afterglow probes in precision biomedicine. This review is expected to provide practical references for the rational design and comparative evaluation of such probes.
The world's increasing demand for petrochemical, pharmaceutical, and nutraceutical products necessitates the development of new strategies for producing these high-value chemicals. The depletion of the natural fossil reserves and environmental pollution associated with their procurement further compel us to find sustainable, greener, and cost-effective alternatives. In light of this, a shift has been witnessed in deriving these products from fossil-based sources or chemical synthesis to biomanufacturing (production using living systems). However, to fully utilize the potential of biomanufacturing, novel tools and strategies that can function in bacteria, archaea, and eukaryotes, regulate multi-enzyme pathways, offer precise and conditional gene regulation, and possess versatility are highly required. This review presents a comprehensive summary of the latest gene modulation tools and strategies used by metabolic engineers, along with a mechanistic overview and their applications. In addition, we presented the tools that have the potential to be used for pathway optimization but are still less explored. Within this context, we categorized these tools based on their molecular level of gene regulation, i.e., at and beyond the central dogma. We believe that a deeper understanding of the design, development, and application of these tools would be beneficial for metabolic engineers to reprogram biosynthetic pathways by adopting system-specific approaches, as a single strategy cannot be applied to all systems. Lastly, we discussed the challenges and future prospects of developing these gene regulatory tools to further advance the biomanufacturing field.
Hydrogels are water-rich, biocompatible three-dimensional polymer networks widely recognized for their ability to control drug release at specific target sites. Among them, in situ forming thermoresponsive hydrogels have emerged as promising injectable platforms for long-acting drug delivery to the posterior segment of the eye. These systems can reduce injection frequency, improve patient adherence, and minimize complications associated with repeated intravitreal dosing. However, the absence of standardized formulation and evaluation methodologies limits clinical translation. This study provides a comprehensive overview of drug-loaded, thermoresponsive hydrogels designed for intravitreal administration. It examines the influence of polymer composition and therapeutic class on key hydrogel properties, including mechanical behavior, safety, and drug-release performance, based on qualitative and quantitative analyses of 35 preclinical studies. Special attention is given to systems achieving prolonged drug release while maintaining biodegradability and biocompatibility. The findings consolidate current evidence and offer guidance for rational formulation design, highlighting how polymer structure and physicochemical characteristics can be tuned to optimize sustained ocular drug delivery and advance translation toward long-acting treatment of posterior segment diseases.
Chemodynamic therapy (CDT) is an emerging cancer treatment that employs transition metal-based nanoagents to catalyze the conversion of elevated intracellular hydrogen peroxide in malignant cells into cytotoxic hydroxyl radicals (•OH) via Fenton-like reactions. Recent developments have also introduced CDT agents that generate singlet oxygen (1O2) through the Russell mechanism. However, current nanoplatforms efficiently produce either •OH or 1O2, but not both, and often exhibit suboptimal catalytic activity, thereby limiting the sufficient production of reactive oxygen species (ROS) required for cancer eradication. This report introduces a ferrous metal-organic framework, Fe(II)-TCPP (tetrakis(4-carboxyphenyl)porphyrin), as the first nanoagent capable of simultaneously and effectively generating •OH and 1O2 through dual catalytic pathways. Its nanoneedle-like morphology increases the surface area and promotes enhanced ROS production. Cell studies demonstrated selective intracellular generation of •OH and 1O2 in cancer cells, resulting in targeted cytotoxicity while sparing non-malignant cells. Systemic administration of Fe(II)-TCPP in a breast cancer mouse model resulted in preferential tumor accumulation, robust intratumoral ROS generation, cancer eradication, and prevention of recurrence without systemic toxicity. These findings mark a foundational advance in CDT nanoagents by integrating Fenton and Russell mechanisms into a single platform, enabling the design of multifunctional catalysts with enhanced ROS output and therapeutic efficacy.
Target-aware molecular generation models hold promise for drug discovery, but it remains unclear whether they genuinely exploit target information or merely resemble the Texas Sharpshooter fallacy by retrospectively rationalizing outputs. To address this, we introduce TarPass, a benchmark comprising a curated dataset of 18 well-studied targets with expert-annotated key interactions and experimentally validated active compounds, enabling fair evaluation of target-aware de novo molecular generation models. We assessed 15 representative models across three paradigms: non-3D, 3D in situ, and optimization-based, considering protein-ligand interactions (PLIs), molecular plausibility, and drug-likeness. Results show that 3D in situ models have a modest average advantage in predicted PLIs. However, many fail to outperform random sampling. Non-3D models, benefiting from broader pretraining, generate more drug-like and synthesizable molecules but exhibit weaker target specificity. Optimization-based methods effectively redirect outputs toward favorable chemical regions for single properties, often at the expense of others, for example by reducing compliance with Lipinski's rules. Integrating these insights, we propose a multi-tier virtual screening workflow for target-aware molecular generation as a post-processing strategy to enrich molecules with improved PLIs and plausibility. Overall, this study highlights the limitations of current models in capturing fine-grained target-specific constraints and provides a standardized framework for future structure-based drug design.
A chitinase-producing bacterium was isolated from a dumping ground soil sample and identified as Bacillus cereus V5331 based on 16S rRNA gene sequencing. The production of chitinase was enhanced through the application of solid-state fermentation (SSF). The effect of variables like pH, temperature, swollen chitin (SC) concentration, moisture content, inoculum size and incubation period were assessed by using a one-variable-at-a-time (OVAT) approach. A central composite design (CCD) using response surface methodology (RSM) was subsequently employed with the chitin concentration, moisture ratio, incubation period and inoculum size as found most effective independent variables. Optimization resulted in a 1.84 fold increase in chitinase production by meeting the parameters: 0.2% chitin, 1:1 moisture ratio, 1% inoculum and 120 h of incubation at 37 °C and pH 7 ± 0.2. The scanning electron microscopy (SEM) studies revealed that chitinase showed significant antifungal action against Candida albicans, causing cell wall disintegration, cell wall inhibition (1.5 cm) and substantial biofilm degradation (53.56%). Chitin breakdown was further confirmed by Fourier transform infrared spectroscopic (FTIR) analysis and p-DMAB assay of the enzyme-treated yeast, which showed the release of 211 µg mL-1 of N-acetylglucosamine (NAG). The current study demonstrates a newly isolated bacterium, which is non-hemolytic (gamma- hemolytic) and producing chitinase constitutively as well as in the presence of chitin in cost-effective locally available media. Further, its anti-fungal potential against C. albicans makes it a promising candidate for future studies to develop an antifungal topical therapeutic agent.
Therapeutic antibodies are widely used in cancer biotherapy due to their target specificity, mediating tumor cell inhibition, angiogenesis suppression, and immune modulation. However, systemic administration often leads to off-target effects, as many antibody targets are also expressed in normal tissues, limiting intratumoral drug concentration and causing adverse events. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while activating host anti-tumor immunity, offer a promising platform for localized antibody delivery. Their inherent tumor tropism, intratumoral administration, and high genetic manipulability enable the engineering of OVs to express exogenous antibodies within the tumor microenvironment, enhancing therapeutic specificity and synergizing oncolytic and immune-mediated effects. In this review, we summarize the biological properties of OVs, strategies for engineering antibody payloads, the mechanistic interplay between OV-induced oncolysis and immune modulation, and current challenges and opportunities for clinical translation. By integrating these aspects, we provide insights into optimizing OV-based antibody therapies for enhanced tumor-targeted efficacy and reduced systemic toxicity.
Saliva is essential for oral lubrication and is influenced by interactions with foods, beverages and pharmaceuticals and their components. We hypothesize that increasing protein concentration increases protein adsorption and therefore reduces measured friction coefficient on the saliva coated tribopair. In this study, we employed our dynamic tribological protocol (DTP) to measure friction coefficient of model bovine serum albumin (BSA) solutions on ex vivo human whole saliva (HWS), saliva pellicle and proline-rich protein (PRP) components of the salivary film. This approach advances current methods that overlook saliva's complexity by testing on bare polydimethylsiloxane (PDMS) surfaces or using whole saliva. Quartz crystal microbalance with dissipation (QCM-D) monitored the mass and viscoelastic properties of these adsorbed layers. We find that BSA concentrations >5.4 mg/ml correlate with decreased friction coefficients across bare PDMS and PDMS coated with the salivary pellicle and PRP layers, suggesting increased protein adsorption. This contrasts with friction measured with whole saliva, which showed no significant difference between samples from 0.6 to 10.4 mg/ml BSA concentration. QCM-D revealed substantial changes in the mass and viscoelastic properties of the adsorbed layers, highlighting a concentration-dependent interaction between BSA and salivary proteins. These interactions suggest that BSA modifies the structural properties and enhances lubrication on the saliva pellicle, impacting oral processing of foods, beverages and pharmaceuticals. These findings expand understanding of salivary lubrication mechanisms and provide an enhanced method for investigating saliva-protein interactions. This offers insight into biophysical changes at oral surfaces during food and pharmaceutical intake, informing the design of products optimized for delivery, mouthfeel, and consumer satisfaction.
Integrated microneedle - iontophoresis (MN - ITP) systems are emerging as a promising approach to improve transdermal drug delivery. These work by dual effect such as mechanical disruption of the stratum corneum along with electrically driven transport. This approach has gained increasing attention for both small molecules and macromolecules, offering the possibility of controlled, minimally invasive administration with improved pharmacokinetic outcomes compared with conventional methods. This review highlights MN - ITP strategies for transdermal delivery, based on a targeted search of major databases, patents, and FDA guidance (1984-2026), emphasizing therapeutic applications since 2015. Different MN-ITP device designs investigated for small molecules as well as larger therapeutics such as peptides, proteins, and vaccines have been discussed. The review focuses on how device design, drug properties, and delivery performance influence outcomes, and compares integrated simultaneous systems with sequential MN - ITP approaches. Current evidence indicates that integrated MN - ITP systems can enhance transdermal delivery, though outcomes depend on drug properties, loading strategies, and electrical parameters. Combined systems often act complementarily rather than uniformly superior, highlighting the need for rational, drug-specific design. Future work should focus on wearable and closed-loop platforms, optimized current density and MN architecture, and clinical translation.
Cystic fibrosis (CF) is an inherited multi-organ disorder. People with CF (pwCF) experience recurrent and chronic lung infections and a progressive loss of lung function. PwCF with poor and rapidly declining lung function may be considered for lung transplantation (LTx), which may improve their quality of life and survival. Nontuberculous mycobacteria (NTM) can cause pulmonary disease in pwCF, and NTM infection is a poor prognostic factor in LTx. Guidelines recommend NTM infection should not automatically preclude LTx. It is important to evaluate the evidence base for LTx in pwCF and NTM pulmonary disease. To evaluate clinical outcomes in pwCF and with NTM infection (NTM infection alone or with NTM pulmonary disease) who undergo LTx by comparing: 1. pwCF with current NTM lung infection who undergo LTx versus those with NTM infection who do not undergo LTX; 2. pwCF with current NTM lung infection who undergo LTx versus those without NTM undergoing LTx. We searched the Cochrane Cystic Fibrosis Trials Register, CENTRAL, MEDLINE, Embase, and PubMed as well as two ongoing trials registries. We checked references. The latest search date was 17 February 2026. We considered non-randomised studies of pwCF (any age) with or without NTM lung infection or disease being considered for LTx as well as studies of pwCF and NTM who either did or did not undergo LTx. Our critical outcomes were mortality, disseminated NTM infection post-LTx, time to chronic lung allograft dysfunction (CLAD), and quality of life at any time points reported. We additionally planned to report lung function, hospitalisations for pulmonary exacerbations, and nutritional parameters in the review. We assessed the risk of bias in three studies using ROBINS-I and in one study using the Joanna Briggs Institute checklist for case series. We could only report results narratively. We used GRADE to assess the certainty of the evidence. We included four single-centre retrospective studies (388 adults). Sample sizes ranged from nine to 177 participants. Mycobacteria abscessus was the most common NTM species identified, and all studies reported infection with other pathogens. All studies compared pwCF and NTM infection to pwCF without NTM infection, all undergoing LTx. Each study reported mortality and disseminated NTM infection post-LTx; two studies recorded CLAD. No study reported quality of life, specific lung function measures (although one study commented briefly on lung function in general), hospitalisations for pulmonary exacerbations, or nutritional parameters. We analysed all NTM infections together for practical reasons and were not able to undertake a planned subgroup analysis by subspecies, but acknowledge that the prognosis and clinical trajectory of pwCF infected with different NTM may not be similar. We downgraded the certainty of the evidence due to non-randomised study design and serious risk of bias across all studies. We assessed all identified evidence as of very low certainty, such that lung transplant may have little to no effect on any of the outcomes listed below, but the evidence is very uncertain. Mortality Two studies (18 participants with NTM) reported similar survival data between NTM-positive LTx recipients and matched controls without NTM. Another study (9 participants) reported that two of five participants NTM-positive at LTx died within a few months post-LTx, whilst one of four NTM-negative participants died three years post-LTx due to chronic rejection. One study (177 participants) found that pwCF who had positive NTM cultures pre-LTx had a longer median survival duration than those who had negative cultures. This study additionally reported on survival of participants with post-LTx NTM infection, finding that the five participants who had post-LTx NTM disease had a longer mean survival duration than the 141 participants without post-LTx NTM disease. Disseminated NTM infection post-LTx In the largest study, of the 18 pwCF with NTM at the time of LTx, seven had at least one positive NTM culture, and four developed NTM disease post-LTx. Conversely, 79 of the 89 pwCF without NTM remained so post-LTx; 10 participants recorded a positive NTM culture, but none developed NTM disease. For the 39 participants without a baseline NTM culture, three participants recorded positive NTM cultures post-LTx, and one developed NTM disease. Of the remaining small studies, one reported that NTM was isolated in four of 13 participants at LTx and in three of these post-LTx. A second study reported that one out of five pwCF had NTM infection post-LTx (all were positive at LTx). The third study reported that five out of nine participants had NTM disease at LTx, and two of these five remained NTM-positive post-LTx. CLAD Two studies assessed CLAD. One study reported that none of the five NTM-positive LTx recipients developed CLAD, stating that the risk of CLAD appeared to be similar between the NTM and the comparator group. The second study stated that three out of nine LTx recipients with NTM disease developed chronic rejection or graft dysfunction. There are no randomised trials to guide clinicians and patients or their families when making decisions regarding LTx in pwCF with NTM. The available data come from observational studies and registry data, often with few people with NTM reported. It has not been possible to pool the available data in meta-analysis, and we are very uncertain of the effect of NTM on pwCF undergoing LTx on the risk of developing NTM disease post-LTx, survival after LTx, and the development of CLAD. The studies were small and at times contradictory. In the era of highly effective modulator treatments, as some centres do not offer LTx to people with a history of NTM, there is an urgent need for more data to guide decision-making. This review is part of a suite of reviews on NTM funded jointly by the CF Foundation and the CF Trust. Protocol registration (2024): www.crd.york.ac.uk/PROSPERO/view/562682.
Supramolecular chemistry provides an efficient and transformative strategy for the modular integration of diverse active pharmaceutical ingredients (APIs) into nanoassemblies through weak, reversible noncovalent interactions, combining the native features of the original molecules with additional functionalities derived from supramolecular structures. Thanks to ultra-high photosensitizer or API loading, on-demand delivery, facile multifunction integration, scalability, and potentially simplified regulatory pathways, supramolecular nanoassemblies markedly enhance the clinical translatability of nanomedicine. In particular, rational design of these systems can overcome hypoxia barriers, revitalizing photodynamic therapy (PDT) against tumors. Despite clinical approval of PDT for cancer therapy over four decades ago, it has yet to achieve widespread adoption as a first-line modality, largely due to the technological bottleneck of tumor hypoxia. In this review, we systematically summarize recent advances in supramolecular nanoassemblies for hypoxic tumor PDT, categorizing them into four key design principles: enriching intratumoral oxygen levels, minimizing oxygen dependence, leveraging tumor hypoxia, and enabling PDT-involved synergistic therapies. We also discuss the intrinsic properties, advantages, and building motifs of supramolecular nanoassemblies. Finally, we highlight current challenges and future perspectives, aiming to broaden the research landscape and accelerate clinical and commercial translation.
The global pharmaceutical drug delivery market is forecasted to grow to USD 2546.0 billion by 2029. The expanding pharmaceutical market urgently needs a more efficient drug research and development paradigm. Artificial intelligence (AI) is revolutionizing drug delivery by offering alternatives to traditional trial-and-error experimental approaches. This review systematically traces the technological evolution from early simple models to current advanced AI algorithms in various applications, ranging from formulation optimization to the prediction of critical formulation parameters and de novo material design. To enhance the reliability of AI applications in drug delivery, we present comprehensive guidelines and "Rule of Five" (Ro5) principles to systematically direct researchers in utilizing AI in formulation development. This "Ro5" includes the following criteria: a formulation dataset containing at least 500 entries, coverage of a minimum of 10 drugs and all significant excipients, appropriate molecular representations for both drugs and excipients, inclusion of all critical process parameters, and utilization of suitable algorithms and model interpretability. The review concludes with insights into emerging trends and future directions, including the utilization of large language models, multidisciplinary collaboration opportunities, talent development, and culture transformation, aimed at facilitating a paradigm shift toward AI-driven drug formulation development.