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Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise’s ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator’s safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration.

Peptides and biologics provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. Most peptides and biologics are fused with cationic uptake moieties or formulated into nanoparticles to facilitate delivery, but these systems typically lack potency due to low uptake and/or entrapment and degradation in endolysosomal compartments. Because most delivery reagents comprise cationic lipids or polymers, there is a lack of reagents specifically optimized to deliver cationic cargo. Herein, we demonstrate the utility of the cytocompatible polymer poly(propylacrylic acid) (PPAA) to potentiate intracellular delivery of cationic biomacromolecules and nano-formulations. This approach demonstrates superior efficacy over all marketed peptide delivery reagents and enhances delivery of nucleic acids and gene editing ribonucleoproteins (RNPs) formulated with both commercially-available and our own custom-synthesized cationic polymer delivery reagents. These results demonstrate the broad potential of PPAA to serve as a platform reagent for the intracellular delivery of cationic cargo. Most reagents designed to deliver cargo into cells are cationic and so cannot deliver cationic cargo. Here the authors show that pretreating cells with the anionic polymer poly(propylacrylic acid) facilitates the uptake and endosomal escape of a wide variety of cationic cargo in numerous cell types.

Macromolecular Drugs (including monoclonal antibodies, recombinant proteins, and nucleic acid therapies) have become a cornerstone strategy for intervening in complex pathological mechanisms such as cancer, autoimmune diseases, and genetic disorders due to their high specificity for disease targets and low off-target toxicity. However, compared to traditional small-molecule drugs, the high molecular weight (>10 kDa) and structural complexity of macromolecular drugs result in extremely low transmembrane permeability. This is particularly challenging in the treatment of central nervous system (CNS) diseases, where the blood-brain barrier (BBB) imposes stringent selectivity, further limiting drug delivery efficiency. This review focuses on the breakthrough strategy of nose-to-brain (NtB) drug delivery. On one hand, the NtB pathway bypasses the BBB, enabling direct CNS drug delivery. On the other hand, nanocarrier technology can synergistically achieve systemic delivery and brain-targeted transport. Based on the latest research advances, this article systematically examines the feasibility of delivering macromolecular drugs via NtB administration. We comprehensively summarize relevant delivery carriers and discuss the potential advantages of intranasal-brain delivery for CNS disease treatment. Notably, while significant progress has been made in this field, further exploration is still needed regarding the mechanisms of NtB delivery and challenges in clinical translation.

Delivery of macromolecules into cells and tissues such as skin is a major challenge. This obstacle poses a particular challenge for the delivery of siRNA where cellular and tissue level transport barriers need to be overcome. siRNAs are potential therapeutics for various dermatological diseases including psoriasis, atopic dermatitis, and cancer; however, their utility is limited by their low absorption across the stratum corneum (SC) and into viable cells of skin. Here, we address this challenge using a peptide identified by phage display termed skin penetrating and cell entering (SPACE) peptide. In vitro studies indicated that the SPACE peptide, when conjugated to cargoes such as small molecules and proteins, was able to facilitate their penetration across the SC into epidermis and dermis. The peptide also exhibited increased penetration into various cells including keratinocytes, fibroblasts, and endothelial cells, likely through a macropinocytosis pathway. The ability of SPACE peptide to deliver siRNA was tested in vivo using two targets, interleukin-10 and GAPDH. Conjugation of the peptide to siRNA led to their enhanced absorption into skin and knockdown of corresponding protein targets.

Polyethylene glycol (PEG) hydrogels are widely used in a variety of biomedical applications, including matrices for controlled release of biomolecules and scaffolds for regenerative medicine. The design, fabrication, and characterization of PEG hydrogels rely on the understanding of fundamental gelation kinetics as well as the purpose of the application. This review article will focus on different polymerization mechanisms of PEG-based hydrogels and the importance of these biocompatible hydrogels in regenerative medicine applications. Furthermore, the design criteria that are important in maintaining the availability and stability of the biomolecules as well as the mechanisms for loading of biomolecules within PEG hydrogels will also be discussed. Finally, we overview and provide a perspective on some of the emerging novel design and applications of PEG hydrogel systems, including the spatiotemporal-controlled delivery of biomolecules, hybrid hydrogels, and PEG hydrogels designed for controlled stem cell differentiation.

Intestinal motility, including peristalsis and segmentation, drives complex fluid movements critical for the oral delivery of biologics and other macromolecules. Despite advances, oral delivery remains commercially limited by low bioavailability, often attributed to poor epithelial permeability. However, variability in motility patterns may also play a critical role, influencing intraluminal distribution and thus absorption, yet this aspect remains underexplored. Here, we combine computational fluid dynamics and machine learning to evaluate how motility type, intensity, pocket size, contractility, and fluid composition affect the delivery of a model macromolecule (insulin) and a permeation enhancer (sodium caprate, C10). We find that segmentation, especially at light intensity, consistently enhances epithelial colocalisation over peristalsis. Under segmentation, smaller pocket sizes (2 mL versus 10 mL) and stronger contractility (occlusion ratio 0.3) yielded optimal performance. Our extreme gradient boosting regression model identified pocket volume, contractility, and motility type as dominant predictors of colocalisation. In a comparative analysis, segmentation led to 128% and 137% higher maximum normalised concentrations of insulin and C10, respectively, than moderate peristalsis with a nutritional drink. Overall, segmentation achieved 6.7-fold and 8.0-fold higher average maximum normalised concentrations for insulin and C10, respectively. These results emphasise segmentation, characteristic of the fed state, as a superior motility pattern for macromolecular absorption compared to peristalsis during the migrating motor complex (MMC). By elucidating the interplay between motility and transport, our findings may guide the design of more effective oral formulations and support personalised strategies for drug delivery based on individual motility profiles.

ABSTRACT Purpose To assess the feasibility of transdermal macromolecule delivery using novel laser-engineered dissolving microneedles (MNs) prepared from aqueous blends of 20% w / w poly(methylvinylether maleic anhydride) (PMVE/MA) in vitro and in vivo. Methods Micromoulding was employed to prepare insulin-loaded MNs from aqueous blends of 20% w / w PMVE/MA using laser-engineered moulds. To investigate conformational changes in insulin loaded into MNs, circular dichroism spectra were obtained. In vitro drug release studies from MNs across neonatal porcine skin were performed using Franz diffusion cells. The in vivo effect of MNs was assessed by their percutaneous administration to diabetic rats and measurement of blood glucose levels. Results MNs loaded with insulin constituted exact counterparts of mould dimensions. Circular dichroism analysis showed that encapsulation of insulin within polymeric matrix did not lead to change in protein secondary structure. In vitro studies revealed significant enhancement in insulin transport across the neonatal porcine skin. Percutaneous administration of insulin-loaded MN arrays to rats resulted in a dose-dependent hypoglycaemic effect. Conclusion We demonstrated the efficacy of MNs prepared from aqueous blends of PMVE/MA in transdermal delivery of insulin. We are currently investigating the fate of the delivered insulin in skin and MN-mediated delivery of other macromolecules.

Succinylcholine (Sch) is the only depolarizing neuromuscular blocking agent widely used for rapid sequence induction in emergency rooms. Unfortunately, a variety of (sometimes lethal) adverse effects, such as hyperkalemia and cardiac arrest, are associated with its use, and currently there are no specific antidotes to reverse Sch or to treat these side-effects. The binding behaviors of Sch and several synthetic receptors, including cucurbit[7]uril, sulfo-calix[4]arene and water-soluble carboxylatopillar[6]arene (WP[6]), were first investigated. With a mouse model, a leathal dose of Sch was selected for evaluation of the antidotal effects of these synthetic receptors on Sch induced mortality. The antidotal effects of a selected synthetic receptor, WP[6], on Sch induced cardiac arrhythmias, hyperkalemia, rhabdomyolysis and paralysis were subsequently evaluated with rat and mouse models. The reversal mechanism was also investigated at a cellular level. All of these macrocyclic molecules exhibited relatively high binding affinities with Sch . In a Sch-overdosed mouse model, immediate injection of these synthetic receptors right after Sch administration increased the overall survival rate, with WP[6] standing out with the most effective antidotal effects. In addition, administration of WP[6] also reversed the paralysis induced by Sch in a mouse model. Moreover, infusion of WP[6] to Sch-overdosed rats reduced the incidence of cardiac arrhythmia, inhibited the otherwise abnormally high serum potassium levels, and relieved the muscular damage. At the cellular level, WP[6] reversed the Sch induced depolarization and reduced the efflux of intracellular potassium. Synthetic receptors, particularly WP[6], exhibited high binding affinities towards Sch, and presented a significant potential as supramolecular therapeutics to treat the various side effects of Sch by specifically sequestering Sch .

Purpose To investigate the efficacy and safety of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model. Methods HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (μ-CT). Results The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint μ-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. μ-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity. Conclusion These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC’s on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis.

The delivery of macromolecules through dermal and transdermal routes presents both significant challenges and transformative opportunities in therapeutic applications. This review highlights the most recent advancements and innovative strategies aimed at overcoming the barriers associated with macromolecular delivery. Cutting-edge approaches such as the use of adjuvants (e.g., hyaluronic acid-based and chemical penetration enhancers), bioactive peptides with diverse functionalities, and mechanical force techniques—including iontophoresis, microneedles, and electroporation—are thoroughly explored. While various strategies have been implemented to enhance skin delivery, they often present significant challenges, particularly for macromolecules. Addressing these challenges requires integrating novel technologies and understanding the interplay between biological barriers and delivery mechanisms. Furthermore, the role of nanotechnology, through systems like nanoemulsions, polymeric nanoparticles, and transferosomes, is examined for its ability to protect macromolecules and regulate their release. Notably, this review provides unique perspectives on the interplay between these strategies and their potential to revolutionise future therapeutics. By highlighting key trends and advancements in macromolecule delivery, this review underscores the importance of innovative approaches in overcoming existing barriers and enabling efficient drug administration. Graphical Abstract