Vascularized skins were 3D printed using single donor human fibroblasts, pericytes, keratinocytes, and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks after grafting with human PBMCs autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection, despite MHC molecule expression on other graft cell types.

Antibody drug conjugates (ADCs) are a burgeoning class of targeted therapies. However, limitations in their synthesis and efficiency of payload delivery restrict their clinical utility. Here we report a supramolecular assembly (SMA) ADC conjugation method, which allows site-specific, uniform drug loading, resulting in an enhanced pharmacokinetic profile and in vivo efficacy. This peptide conjugation strategy relies on spontaneous heterotetrameric coiled-coil formation between a pair of peptides appended on the C-terminus and a drug-loaded complementary pair in aqueous solution. Pairing this SMA conjugation with an antibody that targets the dual-endothlin-1/VEGF signal peptide receptor (DEspR), a pancreatic ductal adenocarcinoma (PDAC) specific receptor, retains antibody binding and plasma stability. When the anti-DEspR monoclonal antibody is conjugated with monomethyl auristatin E (MMAE), the ensuing ADC internalizes following cell surface binding and induces selected cell death in multiple DEspR positive PDAC cell lines. In vivo , the ADC exhibits favorable pharmacokinetics, high tumor specificity, and improves overall survival in a rat orthotopic model of pancreatic peritoneal carcinomatosis, compared to conventional ADC conjugation. A heterotetrameric coiled-coil structure enables the efficient synthesis of a potent ADC, further documenting the versatility of supramolecular scaffolds as key orthogonal building block for site-specific conjugation in biopharmaceutical and biomaterial drug delivery systems. One Sentence Summary:Combining site-specific conjugation of monomethyl auristatin E, via the use of biologically inspired heterotetrameric coiled-coils, with a tumor-selective antibody targeting the dual-endothlin-1/VEGF signal peptide receptor affords a highly effective, ADC, which improves survival in a rat orthotopic model of pancreatic peritoneal carcinomatosis compared to standard cysteine-conjugated analogues with higher drug loading.

Nanoparticle-hydrogel composites hold significant potential for precision medicine. They effectively combine the molecular programming capabilities of nanoparticles with the macroscopic spatial management properties of hydrogels. This review examines the material composition of nanoparticles and hydrogels, the methods used to create composite structures, and the design elements that facilitate therapeutic customization. In theory, these systems can be engineered to target patient-specific biomarkers and coordinate multi-agent release with disease progression while adapting therapeutic dosing to individual treatment contexts that are critical for precision medicine applications. Through analysis of recent advances in cancer immunotherapy, drug delivery, gene therapy, tissue engineering, and personalized vaccination, we emphasize that clinical success demands equal focus on mechanistic sophistication along with practical considerations including manufacturing reproducibility, standardized material characterization, and evaluation frameworks that assess clinically relevant outcomes beyond traditional laboratory metrics. This review discusses the key approaches to strategically designing nanoparticle-hydrogel composites to bridge the gap between preclinical studies and clinical translation in precision medicine.

Inhaled pathogens, pollutants and therapeutics interact with the dynamic architecture of the alveoli, yet how individual particles move and deposit at cellular resolution remains unclear. Here, utilizing the crystal ribcage platform, we track aerosol transport in ex vivo, actively ventilated lungs using real-time fluorescence imaging with single-particle resolution, capturing droplet trajectories, free-flight motion, impact orientation and deposition timescales within functional alveoli. These measurements show that intra-alveolar transport is directional and shaped by airway-guided flow and tissue motion. At larger scales, aerosols do not disperse uniformly throughout the lung's volume but instead concentrate into geometrically constrained clusters of alveoli, forming a conserved mosaic-like compartmentalization while neighbouring alveoli remain largely unexposed. The pattern persists across particle types and species and varies with particle properties and lung age. In models of emphysema, fibrosis and metastasis, airway remodelling alters both the geometry and amount of deposition. These multiscale insights reveal how single-particle transport and airway structure together shape alveolar exposure, immune activation, development and therapeutic accessibility.

Peptide nucleic acid (PNA) is a synthetic mimic of DNA where the deoxyribose-phosphodiester backbone is replaced with N-(2-aminoethyl) glycine units. The lack of deoxyribose-phosphodiester bonds enhances enzymatic stability and improves binding affinity of PNA with complementary DNA and RNA strands. To enhance target binding, conformational stability, and pharmacological activity, several chemical modifications have been introduced into PNA. Modified PNAs have demonstrated promising preclinical potential as antisense and anti-gene agents, supporting their use in diverse biomedical applications. The limited in vivo biodistribution and cellular uptake of PNA have significantly hindered its clinical development. Enhancing PNA biodistribution using nanoformulations and bioconjugate-based delivery strategies has resulted in substantial in vivo pharmacological effects. Further, with advancements in chemistry and delivery techniques, PNA holds promise in treating genetic diseases, metabolic disorders, cancers, and infectious diseases. This review summarizes PNA's pharmacological mechanisms, chemical modifications, delivery strategies, and therapeutic applications while addressing limitations for clinical translation.

Preliminary investigations focused on biodistribution of polymeric nanoparticles (NPs) shortly after ultrasound-guided delivery via the portal vein in early second-trimester fetal rhesus monkeys. Results demonstrated that poly(lactic-co-glycolic acid) (PLGA) NPs (N = 3; 3 mg administered at 75-80 days gestational age) and poly(amine-co-ester)-polyethylene glycol (PACE-PEG) NPs (N = 3; 3 mg at 75-80 days gestational age) distributed to fetal tissues when assessed 24 h post-administration. No adverse findings were observed. PLGA NPs were found primarily in the fetal liver and spleen, whereas PACE-PEG NPs showed more widespread biodistribution to a range of anatomical sites. In another fetal subset with PACE-PEG NPs (N = 2; 90 days gestational age) assessed within 48-h post-administration, results demonstrated enhanced green fluorescent protein reporter mRNA expression in select tissues. These early-stage short-term studies suggest that polymeric NPs, particularly those composed of PACE-PEG, can be safely administered and are potential candidates for fetal delivery of therapeutic nucleic acids. While preliminary, these studies provide evidence to support further investigations in this species to address long-term safety and efficiency.

[This corrects the article DOI: 10.1017/cts.2026.10567.].

Many poly(amine-co-ester) (PACE) nanoparticles, drug delivery vehicles for nucleic acid and small molecule cargoes, accumulate in the liver and spleen following intravenous administration, limiting delivery to nonhepatosplenic tissues. Red blood cell (RBC) hitchhiking, a strategy in which nanoparticles are nonspecifically adsorbed to RBCs prior to administration, has been used to modulate nanoparticle biodistribution, enabling enrichment in organs immediately downstream from the site of vascular infusion. We find that scarcely investigated cellular determinants-namely, storage duration, membrane stiffness, and membrane-bound sialic acid quantity-substantially affect PACE nanoparticle adsorption efficiency. Following development of an optimized adsorption protocol, RBC hitchhiking was shown to enhance PACE nanoparticle cargo delivery to pulmonary tissue while also increasing exposure to other assayed organs. These findings inform future RBC hitchhiking study design, implicate cellular variables as potential obstacles or boons to clinical translation, and demonstrate the delivery of nucleic acids using this strategy with the PACE nanoparticle platform.

Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.

The renal glomerulus is a complex structure in its biology and anatomy and is essential for the physiological maintenance of fluid balance in the body. Glomerular pathologies are prevalent amongst patients with chronic kidney disease, and there are limited therapeutic options for glomerular disease, as well as challenges in diagnosing glomerular dysfunction. Nanoparticles (NPs), due to their tunable physicochemical properties, show great potential in both diagnosing and treating glomerular diseases. To provide a framework for optimizing NP transport within the glomerulus, a rational NP design approach requires a foundation of mathematical models that predict how these physicochemical characteristics impact NP interactions with the glomerular filtration barrier and the glomerular cells. In this review, we discuss the fundamental models of glomerular hemodynamics and nanoparticle transport and how these models may be combined to predict NP transport behavior in glomerular capillaries. We then discuss two cases wherein mathematical modeling may present an opportunity for the rational design of NPs for diagnosing and treating glomerular disease. There are about 2 million glomerului in human kidneys which are the structures responsible for filtering the blood thus initiating the process of urine formation. Diseases of the glomerulus are a leading cause of chronic kidney disease and kidney failure. Nanoparticles are a class of tiny particles that vary in size, such that small nanoparticles are filtered with water in the glomerulus and large nanoparticles are kept inside the capillaries and do not escape as urine. This review focuses on how nanoparticles act in the glomerulus and the mathematical models that can describe these behaviors.

Objectives: Glomerular disease constitutes one of the largest causes of chronic kidney disease, thus targeting the glomerular endothelium with novel therapies is of intense interest to the kidney disease community. Recent work from our laboratory has shown that polymeric nanoparticles functionalized with endothelial cell-targeting antibodies show enhanced binding to the human glomerular endothelium [1, 2] and may provide an effective therapeutic delivery system for glomerular disease. Our objective in this study was to use mathematical modeling to predict which nanoparticle characteristics (e.g. size, charge, density, antibody orientation and affinity) can be tuned to alter their delivery to the endothelium in glomeruli. Methods: We developed a mathematical model that describes the transport of nanoparticles (with associated size, density and surface charge) within a glomerular capillary, that includes a plasma-with-hematocrit compartment, a free plasma compartment, and a wall compartment. Transport rates were estimated using physical equations, taking into account the variance of hematocrit and viscosity of the plasma along the length of the capillary. We then applied this ‘nanoparticle capillary’ model to an anatomically accurate mathematical model of the glomerular capillary network, previously developed by one of us [3, 4]. This model incorporates filtration of plasma through the glomerular capillary wall, hematocrit distribution at network nodes, and plasma protein concentration, as well as alterations in pressure and flow due to renal autoregulation.Results: Our results indicate that nanoparticle size plays a significant role in nanoparticle margination to the wall within our simulated glomerular capillaries, whereas both size and density impact the nanoparticle unbinding from the wall under enhanced shear stress. Anatomical and physiological aspects of glomerular hemodynamics, including the heterogeneity of plasma viscosity and hematocrit throughout the glomerular capillary network, are significant factors that alter nanoparticle delivery to the wall as well as maintenance of nanoparticle binding to the endothelium. Our results indicate that reduction of the efficiency of renal autoregulation minimally impacts nanoparticle binding to the glomerular capillaries, while full amelioration of autoregulation significantly reduces nanoparticle binding to the wall. Conclusions: Myriad factors impact the delivery of nanoparticles to the endothelium of the microvasculature. The glomerulus is a special case in which viscosity and hematocrit change along the length of the capillary network due to filtration, and numerous mechanisms of autoregulation alter the flow and shear stress in individual glomerular capillaries. Our results indicate that nanoparticles can be tuned to optimize their delivery in this environment, thereby providing a basis for design of novel therapies for glomerular disease. Citations: 1. Tietjen, G.T., et al., Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys. Science translational medicine, 2017. 9(418): p. eaam6764.2. Albert, C., et al., Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications. Nature Communications, 2022. 13(1): p. 5998.3. Richfield, O., R. Cortez, and L.G. Navar, Simulations of Glomerular Shear and Hoop Stresses in Diabetes, Hypertension, and Reduced Renal Mass using a Network Model of a Rat Glomerulus. Physiological Reports, 2020. 8(18): p. e14577.4. Richfield, O., R. Cortez, and L.G. Navar, Simulations of Increased Glomerular Capillary Wall Strain in the 5/6-Nephrectomized Rat. Microcirculation, 2021. n/a(n/a): p. e12721.

When exposed to the biological environment, nanoparticles (NPs) form a protein corona that influences delivery profile. We present a study of protein corona formation and NP biodistribution in amniotic fluid (AF) for poly(lactic-co-glycolic acid) (PLGA) and poly(lactic-acid) (PLA) NPs, with and without polyethylene glycol (PEG), as well as poly(amine-co-ester)-PEG (PACE-PEG) NPs. The presence of surface PEG and polyvinyl alcohol (PVA) were characterized to investigate surfactant role in determining protein corona formation. The surface density of PEG groups demonstrated an inverse correlation with the total amount of protein surface adsorption. All PEGylated NPs exhibited a dense brush conformation and demonstrated higher levels of stability in AF than non-PEGylated NPs. The protein corona composition varied by core polymer, while the amount of protein adsorption varied by PEGylation status. In A549 cells, in vitro cellular association of each NP type correlated with the amount of albumin that was found in the protein corona. In vivo, only PEGylated NPs were able successfully distribute to fetal organs, likely due to the enhanced stability imparted by PEG. PLGA-PEG and PACE-PEG NPs had both high levels of albumin in the protein corona and high biodistribution to the fetal lung, consistent with the association with lung cells in vitro. PLA-PEG NPs distributed exclusively to the fetal bowel, which we propose is associated with known gastrointestinal targeting keratin proteins. By furthering our understanding of polymeric NP behavior in AF, this novel study provides a basis for optimization of intra-amniotic NP delivery systems targeting congenital pulmonary and gastrointestinal diseases.

Vascularized skins were 3D-printed using single donor human fibroblasts, pericytes, keratinocytes and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks post-grafting with human peripheral blood mononuclear cells (PBMCs) autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells, and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection despite MHC molecule expression on other graft cell types.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, in large part due to its high resistance to immunotherapies. PDAC is an unresponsive immunological tumor due to low frequency of neoantigens, the immunosuppressive microenvironment, the highly desmoplastic stroma, and low vascularity, all of which highly limit the infiltration of immune cells and therapeutic drugs. Thus, conventional and current approaches, such as immune checkpoint blockades, have shown minimal benefit for PDAC treatment, highlighting the urgent need to develop new therapeutic strategies to reprogram the tumor microenvironment and activate an effective antitumor immune response. We developed TMAB3, engineered from the lupus-derived antibody 3E10, capable of non-covalently binding and protecting RNAs for systemic tumor-targeted delivery. TMAB3 binds RNA with high affinity via a modified nucleic acid-binding pocket and selectively penetrates tumor cells by engaging the ENT2 nucleoside transporter, which is upregulated in PDAC and other malignancies. We complexed TMAB3 with 3p-hpRNA, an immunogenic RNA that activates RIG-I, a cytosolic sensor of viral RNA, triggering type I interferon responses and downstream antitumor immunity. In this study, we demonstrate that the intravenous administration of TMAB3/3p-hpRNA complexes specifically targets malignant cells within PDAC tumors in mice, significantly reduces tumor growth, and triples animal survival after only three acute doses. Furthermore, in orthotopic PDAC, we demonstrate that treatment with TMAB3/3p-hpRNA complexes mechanistically enhances intratumoral CD8+ T cell infiltration and activation, promotes the expression of interferon-stimulated genes, and shifts the immune landscape toward an activated phenotype. Notably, these therapeutic effects were reversed in T cell-deficient (Rag1 knockout) mice, confirming that efficacy depends on adaptive immunity and immunogenic tumor cell death. Additionally, single-cell RNA sequencing of the TMAB3/3p-hpRNA-treated PDAC tumors showed a reduction in malignant cells, upregulation of apoptotic genes, and increase expression of genes associated with an effective and active T cell response. In vitro co-culture experiments also showed that effective T cell activation required tumor cell expression of both ENT2 and RIG-I, highlighting the tumor-specific mechanism of action. Together, these findings introduce TMAB3 as a novel antibody-based platform for the systemic delivery of immunostimulatory RNAs to immunologically quiescent tumors. This strategy overcomes key delivery and immunogenicity barriers in PDAC, thereby unlocking the potential of RNA-based immunotherapies for cancers that are traditionally unresponsive to immune intervention. Diana Martinez-Saucedo, Elias Quijano, Zaira Ianniello, Natasha Pinto Medici, Madison Rackear, Haoting Chen, Luiz Lola-Pereira, Yanfeng Liu, Denise Hegan, Xinning Shan, Robert Tseng, Deanne Yugawa, Sumedha Chowdhury, Minsoo Khang, Wendy S. Woods, Nicholas Gosstola, Ranjit S. Bindra, Marie E. Robert, David A. Braun, Pablo Perez Pinera, W Mark. Saltzman, Luisa F. Escobar-Hoyos, Peter M. Glazer. Systemic targeting of therapeutic RNA into pancreatic tumors via an RNA-binding and cell-penetrating antibody [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A100.

There is intense interest in the advancement of RNAs as rationally designed therapeutic agents, especially in oncology, where a major focus is to use RNAs to stimulate pattern recognition receptors to leverage innate immune responses. However, the inability to selectively deliver therapeutic RNAs within target cells after intravenous administration now hinders the development of this type of treatment for cancer and other disorders. Here, we found that a tumor-targeting, cell-penetrating, and RNA binding monoclonal antibody, TMAB3, can form stable, noncovalent antibody/RNA complexes of a discrete size that mediate highly specific and functional delivery of RNAs into tumors. Using 3p-hpRNA, an agonist of the pattern recognition receptor retinoic acid-inducible gene-I (RIG-I), we observed robust antitumor efficacy of systemically administered TMAB3/3p-hpRNA complexes in mouse models of pancreatic cancer, medulloblastoma, and melanoma. In the KPC syngeneic, orthotopic pancreatic cancer model in immunocompetent mice, treatment with TMAB3/3p-hpRNA tripled animal survival, decreased tumor growth, and specifically targeted malignant cells, with a 1500-fold difference in RNA delivery into tumor cells versus nonmalignant cells within the tumor mass. Single-cell RNA sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited a potent antitumoral immune response characterized by RIG-I activation and increased infiltration and activity of cytotoxic T cells. These studies established that TMAB3/RNA complexes can deliver RNA payloads specifically to hard-to-treat tumor cells to achieve antitumor efficacy, providing an antibody-based platform to advance the study of RNA therapies for the treatment of patients with cancer.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina 1 . Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

Purpose of ReviewFetal therapy, a burgeoning field that encompasses prenatal surgical and medical interventions for congenital diseases, enables minimally invasive strategies of pharmacologic drug treatment before birth. We provide an overview of fetal drug delivery, its connections to current clinical practices, and key aspects for the clinician and researcher developing these approaches.Recent FindingsA growing number of preclinical and clinical studies have demonstrated the success of nanomedicine for fetal applications, which we present here. In addition, we discuss the feasibility of fetal drug delivery from technical and ethical standpoints.SummaryFetal drug delivery still has many areas that require further investigation to understand its full implications. This review provides insights into what is currently known about the feasibility of fetal drug delivery and highlights important ethical considerations as fetal drug delivery continues to improve and advance toward clinical translation.

Abstract The treatment of primary central nervous system tumors is challenging due to the blood–brain barrier and complex mutational profiles, which is associated with low survival rates. However, recent studies have identified common mutations in gliomas [isocitrate dehydrogenase (IDH)-wild-type and mutant, WHO grades II–IV; with grade IV tumors referred to as glioblastomas (GBM)]. These mutations drive epigenetic changes, leading to promoter methylation at the nicotinic acid phosphoribosyl transferase (NAPRT) gene locus, which encodes an enzyme involved in generating NAD+. Importantly, NAPRT silencing introduces a therapeutic vulnerability to inhibitors targeting another NAD+ biogenesis enzyme, nicotinamide phosphoribosyl transferase (NAMPT), rationalizing a treatment for these malignancies. Multiple systemically administered NAMPT inhibitors (NAMPTi) have been developed and tested in clinical trials, but dose-limiting toxicities—including bone marrow suppression and retinal toxicity—have limited their efficacy. Here, we report a novel approach for the treatment of NAPRT-silenced GBMs using nanoparticle (NP)-encapsulated NAMPTis administered by convection-enhanced delivery (CED). We demonstrate that GMX1778 (a NAMPTi) can be formulated in degradable polymer NPs with retention of potency for NAMPT inhibition and anticancer activity in vitro, plus sustained drug release in vitro and in vivo. Direct injection of these drugs via CED into the brain is associated with reduced retinal toxicity compared with systemic administration. Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs.

Background Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein for which there is no cure. One approach to cure CF is to correct the underlying mutations in the CFTR gene. We have used triplex-forming peptide nucleic acids (PNAs) loaded into biodegradable nanoparticles (NPs) in combination with donor DNAs as reagents for correcting mutations associated with genetic diseases including CF. Previously, we demonstrated that PNAs induce recombination between a donor DNA and the CFTR gene, correcting the F508del CFTR mutation in human cystic fibrosis bronchial epithelial cells (CFBE cells) and in a CF murine model leading to improved CFTR function with low off-target effects, however the level of correction was still below the threshold for therapeutic cure. Methods Here, we report the use of next generation, chemically modified gamma PNAs (γPNAs) containing a diethylene glycol substitution at the gamma position for enhanced DNA binding. These modified γPNAs yield enhanced gene correction of F508del mutation in human bronchial epithelial cells (CFBE cells) and in primary nasal epithelial cells from CF mice (NECF cells). Results Treatment of CFBE cells and NECF cells grown at air-liquid interface (ALI) by NPs containing γtcPNAs and donor DNA resulted in increased CFTR function measured by short circuit current and improved gene editing (up to 32 %) on analysis of genomic DNA. Conclusions These findings provide the basis for further development of PNA and NP technology for editing of the CFTR gene.