Extracellular and membrane-associated proteins constitute a substantial therapeutic target space that remains largely inaccessible to intracellular degradation strategies based on the ubiquitin-proteasome system. Membrane and extracellular targeted protein degradation (meTPD) addresses this limitation by coupling target recognition to degradation-competent uptake and intracellular sorting rather than relying on a single receptor or platform. In this Review, we organize meTPD strategies according to their trafficking and degradation routes, including lysosome-targeting receptor-dependent systems, transmembrane E3 ligase recruitment, receptor-independent internalization, lysosomal-sorting sequences and autophagy-mediated clearance. We then examine how ligand affinity and epitope accessibility, ternary-complex geometry, linker architecture, covalency, valency, receptor recycling and degrader reuse collectively determine productive degradation. Particular attention is given to spatial selectivity across tissues, cell populations and subcellular organelles, as well as to artificial intelligence-assisted design, stimuli-responsive activation and delivery systems that regulate the exposure and trafficking of meTPDs. Finally, we discuss emerging clinical evidence, convergence with antibody-drug conjugate-derived modalities, the hook effect and plausible resistance mechanisms. By integrating molecular design, receptor biology, intracellular trafficking, delivery and pharmacodynamic considerations, this Review provides a framework for selecting disease-matched degradation routes and advancing meTPDs from platform-specific demonstrations towards predictable therapeutic modalities.
Cardiovascular disease remains the leading cause of death worldwide. However, the limited translational fidelity of traditional preclinical models continues to constrain the development of safer and more effective therapies. Animal studies and static two-dimensional cultures only partially reproduce human cardiac physiology, including mechanical loading, perfusion, multicellular interactions, and drug metabolism, which contribute to late-stage failure and unexpected cardiotoxicity. Accordingly, there is a growing need for human-relevant platforms that can more accurately model cardiac (patho)physiology, support drug discovery, and improve safety assessment. Microfluidic heart-on-a-chip (HoC) systems address this need by combining microfabrication, tissue engineering, and controlled fluid flow to generate miniaturized cardiac tissues with physiologically relevant biochemical, mechanical, and electrical cues. These platforms can provide real-time functional readouts, including contractility, electrophysiology, calcium handling, metabolic activity, and biomarker release, while also enabling the study of disease-relevant phenotypes such as ischemia-reperfusion injury, arrhythmias, fibrosis, and cardiomyopathy. In addition, HoC systems are increasingly being integrated with biosensors, automation, and multi-organ configurations to capture drug metabolism and inter-organ crosstalk, further improving their predictive value for efficacy and toxicity screening. In this review, we summarize the core design elements of microfluidic HoC platforms, highlight their applications in cardiovascular drug discovery and cardiotoxicity assessment, and discuss current challenges and future directions for the field.
Stimuli-responsive polymer systems have been rapidly gaining attention for the targeted release of therapeutics. Such systems often require the construction of complex, multi-functional materials. Advancements in click and bioorthogonal reactions have therefore been increasingly used to prepare these polymeric materials, both through their synthesis in the lab as well as in their assembly in vivo at the target site. Furthermore, such reactions can even be used to trigger therapeutic release. This review will cover the main bioorthogonal and click reactions used for polymeric delivery systems including copper(I)-catalyzed azide-alkyne cycloaddition, strain-promoted cycloadditions, inverse electron demand Diels-Alder reactions, imine and hydrazone formation, and reactions of thiols such as thiol-ene, thiol-yne, thiol-Michael, and disulfide exchange. It will also provide an overview of the most important stimuli used to actuate drug release including changes in pH or redox status, enzymes, and external stimuli such as heat and light. The applications of this chemistry in a range of polymeric systems including polymer-drug conjugates, nanoparticles, polyion complexes, hydrogels, and nanogels will then be discussed. Finally a perspective of the current status of the field, challenges and areas for future exploration will be presented.
Patient-centric Biologics-Device Combination Products (BDCP) improve patient experience and compliance, while enhancing therapeutic outcomes by enabling novel routes of delivery, tackling frequent dosing and large-volume delivery requirements, and/or by simplifying administration in a healthcare setting as well as in out-patient dosing (e.g. self-administration). They also present promising solutions to overcome vaccine immunization challenges, particularly in developing nations. The BDCP opportunities, however, are often tempered by intrinsic properties of biologics (e.g. stability, viscosity etc.) and devices (e.g. design control, human factor engineering etc.) which can be further compounded by regulatory complexity across multiple jurisdictions. This comprehensive review examines the current landscape of combination product spanning across the complexities of modality (e.g. proteins, vaccines, oligonucleotide, mRNA/lipid nanoparticle (LNP) and to a limited extent cell & gene therapy) and delivery (parenteral, oral, ocular etc.) through the lens of business drivers, phase-appropriate technical development, regulatory frameworks, and patient-centric design principles. Selected case studies and commercially approved products for each modality are also presented here. Continued investments in new and improved devices such as prefilled syringes, wearable pumps, pen devices, jet devices and autoinjectors for liquid and lyophilized products highlight the recent paradigm shift for integration of delivery devices from self-administration to personalized medicine. Persistent innovation in the field, for example, has enabled device integration beyond chronic conditions such as diabetes and autoimmune diseases and prophylactic vaccination such as flu to cancer immunotherapy. Furthermore, technical, clinical and regulatory successes in achieving novel routes of delivery (e.g. oral biologics, inhaled insulin, inhaled vaccines, intradermal vaccination etc.), smart delivery systems and digital technologies have further advanced the boundaries of BDCP to not only increase market penetration but create new markets. This not only benefits patients worldwide but also paves the way for precision medicine in the future.
Peptide-drug conjugates (PDCs) are emerging as a next-generation class of targeted therapeutics designed to overcome key limitations associated with conventional chemotherapy and antibody-drug conjugates (ADCs). By integrating a tumor-homing peptide, a cleavable or stimuli-responsive linker, and a potent cytotoxic payload, PDCs offer enhanced tumor selectivity while maintaining structural simplicity and synthetic flexibility. Compared to bulky monoclonal antibody-based systems, PDCs possess significantly smaller molecular size, enabling improved tumor penetration, rapid tissue diffusion, and reduced immunogenicity. Recent advances in peptide engineering have facilitated the development of ligands targeting integrins, G protein-coupled receptors, and other tumor-overexpressed biomarkers, promoting receptor-mediated internalization and intracellular drug release. Linker chemistry plays a pivotal role in therapeutic performance, with enzyme-sensitive, redox-responsive, and pH-cleavable linkers enabling site-specific drug activation within the tumor microenvironment. Despite their promise, PDCs face challenges including rapid renal clearance, proteolytic degradation, and limited circulation half-life. Strategies such as cyclization, PEGylation, and albumin-binding modification have been explored to enhance stability and pharmacokinetics. Furthermore, emerging theranostic PDC platforms incorporate imaging moieties or radiolabels, enabling real-time visualization of tumor targeting, biodistribution, and treatment response. Such dual-functional systems facilitate biomarker-guided patient stratification and image-guided precision therapy. This review comprehensively discusses the structural design principles, delivery barriers, pharmacokinetic considerations, applications, imaging advancements, and current clinical landscape of PDCs, highlighting their advantages over ADCs and outlining future directions for precision oncology. Collectively, PDCs represent a promising and versatile platform poised to redefine targeted cytotoxic delivery in cancer therapy.
The use of nanoparticles (NPs) for delivery, particularly for nucleic acid-based therapeutics has become a central determinant of therapeutic efficacy. To ensure safety, potency, and manufacturability across drug development stages, the physicochemical properties of NPs need to be precisely controlled. Microfluidic (MF) synthesis enables great control over the NPs formation process and maintains physicochemical properties across different production scales. MF offers economic advantages for high-throughput screening of large formulation libraries, while delivering superior reproducibility and scalability to meet regulatory requirements. In this review, we map the end-to-end workflow of MF based NPs synthesis and present an integrated "toolbox" of technologies to optimize this process for successful drug development. We highlight advances in chip fabrication methods and the critical performance tests required to ensure robust NPs production. We then detail the underlying principles of NPs formation in MF systems and highlight emerging computational and simulation approaches to model and predict NPs assembly. Finally, we examine the incorporation of machine learning tools to establish predictive relationships between process parameters and NPs properties. We anticipate that strategic selection of MF chip design, integrated with chip fabrication technologies, simulation-based approaches, and machine learning tools, can greatly boost experimental optimization, process control, and predictability, ultimately accelerating the clinical translation of NPs-based therapies.
Multidrug resistance (MDR) in colorectal cancer (CRC) arises from interacting tumour-cell, pharmacological and microenvironmental programmes that undermine both drug activity and delivery. Chemotherapy-associated MDR is the principal focus of this review, while resistance to targeted therapy and immunotherapy is considered where it directly affects delivery design or patient selection. Bioactive compounds can modulate several resistance pathways, but their translational value is constrained by poor solubility, instability, rapid metabolism and inadequate exposure at resistant lesions. This review critically examines when nanomedicine can make such mechanistic activity pharmacologically and translationally meaningful. We link resistance biology to delivery functions, evaluate bioactive chemosensitiser candidates against human exposure, compare major nanomedicine design strategies, and assess nano-bio interactions, repeat-dose safety, manufacturing and clinical positioning. Across the evidence, three limitations recur. First, concentrations associated with chemosensitisation for curcumin, resveratrol, epigallocatechin gallate and quercetin generally exceed measured human parent-analyte exposure. Second, many resistance claims rely on parental or poorly characterised models, whereas studies combining defined resistance provenance with functional mechanism and exposure confirmation remain uncommon. Third, human studies demonstrate feasibility, tissue exposure or treatment response, but not mechanism-specific reversal of CRC MDR by a bioactive compound or bioactive nanomedicine. Progress therefore depends less on adding new particle classes than on matching a necessary formulation function to a defined resistance or spatial barrier, quantifying active exposure in the relevant compartment, validating mechanism in appropriate models, and integrating repeat-dose safety, scalable manufacturing and biomarker-guided clinical development.
Cancer progression is closely associated with dysregulated redox homeostasis within the tumour microenvironment (TME), where reactive oxygen and nitrogen species influence tumour survival, immune evasion, and therapeutic resistance. While physiological redox signalling supports antitumour immunity, persistent oxidative stress promotes immunosuppression and limits the efficacy of immunotherapies, making redox modulation an attractive therapeutic strategy.Naturally occurring polyphenols have emerged as promising redox-regulating agents due to their antioxidant, anti-inflammatory, and immunomodulatory properties. Beyond scavenging reactive species, they regulate pathways involved in immune activation, metabolic reprogramming, ferroptosis, and tumour-immune interactions. However, their clinical application is hindered by poor bioavailability, rapid metabolism, and limited tumour accumulation.Nanotechnology-based delivery systems, including liposomes, polymeric nanoparticles, metal-based nanoplatforms, biomimetic vesicles, and stimuli-responsive carriers, have been developed to overcome these limitations. These platforms enhance polyphenol stability, targeted delivery, and controlled release while enabling synergistic interactions with immunotherapy. Importantly, they can function as programmable redox-immunomodulatory systems capable of remodelling the TME, inducing immunogenic cell death, promoting ferroptosis, and activating innate and adaptive immune responses.This review discusses the interplay between redox regulation and tumour immunity, examines the immunomodulatory mechanisms of polyphenols, and highlights recent advances in nanocarrier-based delivery strategies. Challenges related to biological heterogeneity, biomarker development, manufacturing scalability, regulatory approval, and clinical translation are also considered, together with future perspectives for precision redox medicine based on polyphenol-enabled nanotechnologies.
Organs-on-chips (OoCs) are miniaturized devices for culturing and stimulating living cells within microscopic fluidic environments to create minimal organ surrogates. For the last decade, a diverse range of organ models were reconstructed at the micron scale to support the investigation of fundamental biological processes. By more accurately replicating the pathophysiology of human health, OoCs can serve as alternatives to conventional 2D cell culture and animal models for drug testing. However, moving from a research prototype to a commercially viable model system requires consideration of materials and manufacturing methods to simultaneously sustain high biological fidelity of organ mimicries, while enabling fabrication at scale. This review synthesizes recent advancements in that regard: We provide an overview of materials exhibiting relevant functional properties, their associated manufacturing methods, considerations of metrology and biocompatibility, and showcase representative examples of disruptive OoCs technologies currently integrated in the drug development pipeline to accelerate the discovery of safer and more effective therapeutics.
After nearly five decades of clinical dominance, polyethylene glycol (PEG) is approaching an inflection point. Pervasive environmental exposure has driven anti-PEG antibody prevalence above 70% in some adult populations, transforming the once-reliable stealth shield into a source of accelerated blood clearance (ABC), complement activation-related pseudoallergy (CARPA), and unpredictable loss of efficacy - risks brought into sharp focus by the global rollout of PEGylated lipid nanoparticle mRNA vaccines. PEG is thus no longer a passive bystander, and a generation of drug delivery scientists are responding by re-engineering the corona itself. This review reframes stealth not just as bioinert concealment, but rather as an active interface between a nanomedicine and the host: a programmable surface that can hide, sense, switch, deliver, and target. We examine how branched, bottlebrush, and statistical PEG architectures evade pre-existing antibodies while preserving regulatory familiarity; how dePEGylation triggered by tumour pH, redox, enzymatic, and reactive oxygen species (ROS) cues turns stealth into a temporally controlled handoff; how classical alternatives and new functional stealth polymers of zwitterionic, polyglycerol, and polysulfoxide chemistries deliver ultra-long circulation while simultaneously providing immune tolerance, cryo/lyoprotection, or antioxidant defense; how degradable platforms (heparosan, polyphosphoester, hydroxyethyl starch, PASylation, XTEN, EK zwitterionic peptides) reconcile prolonged half-life with clean metabolic exit; and how bio-inspired tropic coatings - hyaluronic acid, phosphocholine, phosphoserine, fucoidan, sialic acid, glucose and mannose glycopolymers - exploit endogenous receptors to reconcile stealth properties with directional targeting.
PEGylation is a crucial strategy in modern nanomedicine, offering effective and safer therapeutics. However, the growing prevalence of anti-PEG antibodies (APAs) in patients has raised critical concerns, with multiple studies demonstrating reduced clinical efficacy and safety risks associated with APA formation. This has generated broad consensus on the need for next-generation nanomedicine solutions, leading to the development of several promising alternatives to PEG. However, antibodies against some alternatives have already been reported. Furthermore, full understanding of PEG immunogenicity and clinical impact is highly relevant before switching to another polymeric structure. Therefore, a detailed consideration of immunogenicity and molecular recognition patterns is recommended to guide the next generation of nanomedicine. To address these challenges, the randomized PEG (rPEG) technology has recently been introduced, capitalizing on APA structure knowledge. The random incorporation of "synthetic point mutations", i.e., glycidyl methyl ether, disrupts the regularity of PEG, while preserving the polyether key properties. Reduced antigenicity of rPEG was confirmed via ELISA, MST, and FCS analysis. Further in vitro studies demonstrated that rPEG is noncytotoxic, does not interact with blood, and is unlikely to activate complement. In nanoparticle applications, rPEG-based polymeric micelles and lipid nanoparticles exhibited reduced antigenicity and comparable mRNA transfection efficiency to their PEGylated counterparts, respectively. Recent in vivo studies demonstrated that rPEG-liposomes, across a series of PEG alternatives, were the only formulations that did not exhibit accelerated blood clearance, even following cross-immunization with PEGylated liposomes. Although stealth performance requires further optimization, rPEG represents a highly promising PEG alternative.
Messenger RNA (mRNA) therapeutics have emerged as a transformative biomedical platform with broad potential in vaccination, protein replacement, gene editing, and cancer immunotherapy. Despite substantial progress, the broader clinical translation of mRNA therapeutics requires further optimization of delivery systems to address challenges related to stability, biodistribution, intracellular delivery efficiency, and biosafety. In this review, we discuss the rational design of redox-responsive nanomaterials that exploit physiological intracellular redox compartmentalization or, in selected systems, disease-associated oxidative or reductive dysregulation to improve mRNA delivery. We first summarize the biological basis of redox-responsive delivery by linking disease-associated redox imbalance with the engineering principles of responsive nanomaterials. We then systematically discuss major classes of redox-responsive systems, including oxidation-responsive, reduction-responsive, and dual-responsive platforms across polymeric, lipid-based, and hybrid nanomaterial formulations. Particular emphasis is placed on how distinct chemical architectures and responsive motifs influence intracellular delivery behavior, cargo release, immune compatibility, and therapeutic performance. Finally, we discuss current translational challenges, including long-term biosafety, repeated administration, immunogenicity, and large-scale manufacturing, while highlighting emerging opportunities such as AI-assisted material design and personalized theranostic applications. Collectively, this review provides a comprehensive framework for understanding how redox-responsive nanomaterial engineering may advance the next generation of precise and clinically translatable mRNA therapeutics.
In vivo reprogramming of T cells represents a transformative approach in immune-based therapies, with the potential to overcome the limitations of traditional ex vivo-engineered T cell products, such as autologous CAR-T therapies. While CAR-T cells have achieved remarkable success in treating hematological cancers with several FDA approved products, challenges like manufacturing complexity, costs, toxicity, and relapse rates persist. In this review, we first provide a brief background on T cell biology and CAR T cells, and then present a comprehensive overview of emerging strategies for direct in vivo T cell reprogramming. We discuss the key platform technologies, including lipid nanoparticles and viral vectors, and the targeting methods employed to enhance delivery and efficacy. Moreover, we evaluate the functional state of reprogrammed T cells and the role of different mouse models and reporter systems in assessing their therapeutic potential. We highlight key challenges related to the biodistribution, activation, and persistence of modified T cells, with an emphasis on the potential of these strategies for treating not only blood cancers but also solid tumors, autoimmune diseases, and beyond. Finally, we provide an outlook on future directions by highlighting recent non-human primate studies, ongoing clinical activities, and strategic acquisitions, representing key innovations and discuss remaining translational hurdles in the field.
Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), globally pose a significant challenge with an aging population. Despite the presence of various therapeutic agents, AD and PD treatments with small molecules currently only address the symptoms; certain biologic agents for AD have been approved for their disease-modifying effects, but the risk of intracerebral hemorrhage severely limits their use. Moreover, the bioavailability of orally administered agents in the brain is challenged by the blood-brain barrier, complicating brain-targeted drug development. Extensive efforts are currently underway to develop intranasal platforms with nanoparticles for direct nose-to-brain drug delivery. Additionally, various in vitro designs involving brain organoids, and in vivo models, such as rodents and zebrafish, have been explored to improve the efficiency and accuracy of preclinical models. Efforts to develop sophisticated computational modeling of intranasal drug delivery, including computational fluid dynamics (CFD) deposition and physiologically based pharmacokinetics (PBPK) modeling, also continue to advance the intranasal drug delivery research and potentially improve the feasibility of developing clinically relevant intranasal platforms for neurodegenerative disease.
In recent years, heavy-atom-free photosensitizers have been recognized as an important class of agents for photodynamic therapy (PDT). In particular, redox-activated heavy-atom-free photosensitizers inspired by the redox imbalance of the tumor microenvironment are emerging as a promising strategy to improve the specificity and therapeutic efficiency of PDT. This review highlights design strategies of redox-activated heavy-atom-free photosensitizers (PSs), including donor-acceptor-based frameworks, thionation, aggregation-induced emission (AIE) driven intersystem crossing enhancement, and the integration of responsive moieties for reactive oxygen species (ROS), glutathione (GSH), cysteine (Cys), and hydrogen sulfide (H₂S). In addition, recent advances in the development of redox-activated heavy-atom-free PSs over the past three years are summarized. Finally, main challenges, including hypoxic tumors, limited tumor-targeting efficiency, and limited light penetration into deep-seated tumors, as well as future prospects for this field, are discussed.
Proteolysis targeting chimeras (PROTACs) occupy a challenging oral developability space defined by high molecular weight, elevated polarity and lipophilicity, and substantial conformational flexibility, placing many candidates beyond conventional oral drug-likeness criteria and frequently within Biopharmaceutics Classification System (BCS) class II or IV. These properties create modality-specific constraints in solid-state behaviour, solubility and supersaturation, permeability, and intestinal transport, which together can limit oral absorption and contribute to variable systemic exposure. Many PROTACs exhibit low aqueous and biorelevant solubility, inconsistent maintenance of supersaturation, and uncertain effective permeability complicated by non-specific binding, efflux, and assay-related artefacts, thereby hindering early developability assessment and physiologically based biopharmaceutics modelling (PBBM). To support phase-appropriate development, we propose an early, flexible quality target product profile (eQTPP) framework to guide formulation selection, define evidence requirements for progression, and inform clinical bridging strategy. Within this context, the review evaluates clinically deployable enabling formulation strategies. Solubilisation approaches based on co-solvents, surfactants, and cyclodextrins can increase dissolved concentrations, although their utility is often limited by precipitation on dilution and poor translation to oral solid dosage forms. Lipid-based formulations, including self-emulsifying and supersaturated systems, align with the high lipophilicity of many PROTACs and can improve solubilisation and, in selected cases, permeability or lymphatic access, but may introduce challenges in drug loading, capsule compatibility, and fill stability. Amorphous solid dispersions offer a versatile approach to enhancing dissolution and sustaining supersaturation with favourable manufacturability potential, although polymer-bile interactions and species-dependent effects can generate in vitro-in vivo disconnects. Permeation enhancement remains a secondary strategy constrained by safety, dose, and formulation complexity. The review then considers clinical translation, including fed/fasted state, acid-reducing agent effects, and PBBM-informed bridging, before briefly highlighting future opportunities for local delivery. We therefore propose pragmatic decision frameworks integrating physicochemical characterisation, biorelevant testing, and PBBM to support formulation selection and translation. Overall, successful oral PROTAC development depends on selecting the simplest phase-appropriate enabling strategy that addresses the dominant absorption bottleneck while minimising development risk.
High-concentration biologics are transforming patient care by making potent injectable therapies easier and more accessible. But these biologics come with real stability hurdles. Proteins at these concentrations are more prone to clumping, misfolding, and aggregation that can undermine the drug product's safety and effectiveness. Silicone oil, a common syringe lubricant, helps ensure smooth injections but often leaches and migrates into the drug solution. Hydrophobic protein regions adsorb at oil-water interfaces, nucleating smaller aggregates that propagate into larger ones under agitation. Continued exposure to leached silicone oil during storage/ transport can accelerate the generation of protein particles. These particles have the potential to increase immunogenicity in patients, making this a significant risk from both clinical and regulatory perspectives. To combat these issues, innovative solutions such as advanced coatings, protective surfactants, optimized buffer systems, and silicone oil-free syringes are being explored, alongside device engineering and gentler process controls. Together, smarter formulation choices, device breakthroughs, and streamlined processing will pave the way for safer, more stable high-concentration biologics in next-generation syringe systems. This review provides a brief overview of silicone oil characteristics and its interactions with proteins, and discusses possible solutions to minimize silicone oil-induced protein aggregation.
Targeted protein degraders (TPDs), including proteolysis-targeting chimeras (PROTAC) and molecular glue degraders (MGD), are among the most promising small-molecule-based drug treatments in oncology. The May 2026 U.S. Food and Drug Administration (FDA) approval of vepdegestrant provides a regulatory milestone for heterobifunctional protein degradation and for PROTAC therapeutics. First-generation TPDs were developed for oral delivery; however, the intrinsic physicochemical properties of TPDs impose constraints on their oral bioavailability, systemic exposure, target-site accumulation, and therapeutic efficacy. As the field transitions toward a second wave of TPD development, nanoparticle-based targeted protein degraders (nano-TPD) are gaining momentum for broadening the therapeutic landscape of protein degradation. In this context, drug delivery systems offer opportunities to overcome key translational barriers by improving pharmacokinetics, tissue distribution, target site localization, cellular uptake, and therapeutic index. Here, we provide an overview of TPD discovery, from early laboratory to (pre-) clinical progress, discuss translational challenges, and suggest advanced drug delivery solutions to help realize the full potential of TPD therapies.
Polyethylene glycol (PEG) is widely used to improve the stability, solubility, and circulation half-life of nanoparticles, proteins, and small-molecule drugs. However, anti-PEG antibodies are increasingly recognized as a clinically relevant variable that can reshape the in vivo fate of PEGylated therapeutics, contributing to accelerated blood clearance, altered biodistribution, loss of efficacy, and, in a subset of individuals, hypersensitivity. This review integrates molecular, formulation, and host determinants of PEG immunogenicity using evidence from preclinical models and human studies. We summarize the prevalence and sources of pre-existing anti-PEG antibodies, including environmental exposure and host genetic associations, and discuss how antibody binding remodels the biomolecular corona, engages Fc- and complement-mediated pathways, and promotes phagocytic uptake that undermines PEG-mediated "stealth". We then evaluate mitigation strategies spanning polymer and lipid design, emerging PEG alternatives, and patient-centered approaches such as baseline antibody profiling and pre-treatment with free PEG in animal models. Finally, we highlight an emerging paradigm that exploits anti-PEG binding for benefit: bispecific anti-PEG antibodies and sequential pre-targeting strategies that convert PEG into a modular handle for active targeting across polymer nanoparticles, liposomes, and mRNA-lipid nanoparticles. Together, this review frames anti-PEG immunity as a central design variable in nanomedicine, linking PEG-mediated stealth, circulation time, targeting efficiency, biomolecular corona formation, and immune recognition. We propose guiding principles for deciding when PEG should be retained and optimized, replaced with alternative stealth materials, managed through patient-level screening or pre-treatment, or deliberately exploited as a modular handle for targeted delivery.
Lysosome-targeting degraders (LYTADs) are bifunctional molecules that harness lysosomes to degrade pathogenic proteins. This breakthrough technology addresses a gap in cell membrane- and extracellular protein-targeted degradation technologies. Together with proteolysis-targeting chimeras, LYTADs have driven the development and application of targeted protein degradation (TPD) in biomedicine and other fields, making it one of the most prominent chemical biology technologies of the 21st century. Currently, LYTAD technology has been extensively researched and expanded, demonstrating its ability to degrade a variety of pathogenic proteins across cells, tissues, and diseases, and is not limited to TPD. LYTADs are now in the critical stage of translating their concepts into clinically validated drugs. Many emerging limitations and challenges cannot be addressed through structural design and optimization alone. With the increasing demand for accelerated clinical translation, delivery systems are being used to improve the physicochemical properties of LYTAD molecules in both in vivo and in vitro settings. By combining delivery system design strategies with LYTAD design, or by harnessing delivery systems to deliver LYTADs, the targeting capabilities, therapeutic effects, and biosafety of LYTADs can be enhanced. This integration of delivery systems and LYTADs brings new breakthroughs and opportunities to the field of TPD. In this review, we summarize recent advances in LYTAD delivery systems, focusing on design strategies and biomedical applications. We will also discuss the current challenges and envision future development opportunities of this technology in the biomedical field.
