Every entry summarises what the study set out to test, what it found and why it changes how we design delivery systems. Browse research and reviews or search the collection.
Jacobs W, De Zwaan K, Rutten L, Van Wessel T, Boltje Tj, Cano Lq, Et Al.
Non-viral nanocarriers for oligonucleotide delivery have enormous therapeutic potential, but the factors determining cell type-specific uptake remain incompletely understood. One major cell surface component that delivery vectors encounter is the glycocalyx. While membrane glycans are established interactors for many viruses, their impact on non-viral particles has remained underexplored. Here, we show that the role of membrane glycosaminoglycans (GAGs) in mRNA delivery differs across nanocarrier categories and cell types.
Kumar A, Patri Sv, Chilumula S, Arjunan P, Ayyanar V, Hanchate P, Et Al.
The clinical effectiveness of doxorubicin (DOX) in hepatocellular carcinoma (HCC) remains constrained by poor tumor selectivity and the emergence of multidrug resistance. In this work, we examine how the electronic nature of the C-5 substituent on uracil-based nucleoside lipids shapes the physicochemical and biological behavior of DOX-loaded lipid nanoparticles (LNPs).
This review surveys lipid nanoparticle composition, ionisable lipid synthesis and strategies to target delivery of fragile RNA therapeutics while addressing tissue selectivity and immune activation.
Kelsey L. Swingle, Margaret M. Billingsley, Sourav K. Bose, Brandon White, Rohan Palanki, Apeksha Dave, Savan K. Patel, Ningqiang Gong, Alex G. Hamilton, Mohamad-Gabriel Alameh, Drew Weissman, William H. Peranteau, Michael J. Mitchell
Congenital protein deficiencies often begin irreversible pathology in utero, but postnatal treatments are limited. In utero mRNA delivery could enable protein replacement before disease onset, yet LNP stability in fetal amniotic fluid and how it affects mRNA delivery had not been previously investigated. LNP A12 was most stable in mouse amniotic fluid; A1 was least stable. A12 had significantly higher bound protein content than A1 (p < 0.0021). - Percent change in PDI inversely correlated with in vitro luciferase.
Drug carriers are as important as drugs themselves, but clinical translation of polymeric nanocarriers (PNCs) remains limited by incomplete understanding of how carrier architecture and physicochemical properties affect loading, circulation, targeting, and release. The review addresses this gap by systematically linking structural varieties of PNCs and their physicochemical properties to drug delivery profiles, and by highlighting. Representative quantitative findings highlighted in the review: - Aspect ratio and uptake: cylindrical particles with aspect ratio 3 were internalised about 4-fold faster than aspect ratio 1 particles in HeLa cells,.
Farough Marofi, Roza Motavalli, Vladimir A. Safonov, Lakshmi Thangavelu, Alexei Valerievich Yumashev, Markov Alexander, Navid Shomali, Max Stanley Chartrand, Yashwant Pathak, Mostafa Jarahian, Sepideh Izadi, Ali Hassanzadeh, Naghmeh Shirafkan, Safa Tahmasebi, Farhad Motavalli Khiavi
CAR T cell therapy has transformed treatment of hematologic malignancies, but its efficacy in solid tumours remains unsupported. Solid tumours present distinct barriers—antigen heterogeneity, poor T cell trafficking/infiltration, and an immunosuppressive tumour microenvironment (TME)—that limit CAR T cell function. This review addresses these barriers and evaluates emerging strategies to improve CAR T cell therapy in non-hematologic malignancies. --- - Ovarian cancer: MSLN-CAR NK cells significantly killed MSLN⁺ ovarian cancer cells (SK-OV-3, OVCAR-3) *in vitro*. MUC16-specific CAR T cells eradicated malignant cells in mouse models. TAG72-CAR T and FRα-CAR T inhibited ovarian cancer growth. - Breast cancer: MUC28z CAR T cells (targeting tMUC1) reduced TNBC tumour proliferation and survival in a xenograft model. HRG1β-based CAR T cells inhibited breast cancer via HER family receptors. Anti-HER2 CAR T cells triggered cell death in HER2-overex
CAR-T cell therapy has produced remarkable clinical responses in certain B cell leukemias and lymphomas, but major limitations remain—including life-threatening toxicities, limited efficacy in solid tumours, antigen escape, poor persistence/trafficking, and an immunosuppressive microenvironment. This review addresses these barriers and discusses recent innovations in CAR-T engineering to improve efficacy and safety in both haematological malignancies and solid tumours. --- - Antigen escape: 70–90% of relapsed/refractory ALL patients show durable responses to CD19 CAR-T, but 30–70% of recurrent disease involves CD19 downregulation/loss. BCMA loss also observed in multiple myeloma. - Dual targeting: CD19/CD22 and CD19/BCMA dual-targeted CAR-T cells show promising efficacy and favourable safety in early clinical trials. Tandem HER2/IL13Rα2 CARs improved anti-tumour activity and decreased antigen escape in glioblastoma models. - Toxicity reducti
Zhaoting Li, Yixin Wang, Yingyue Ding, Lauren Repp, Glen S. Kwon, Quanyin Hu
Immunotherapy has limited response rates and systemic side effects, and synthetic drug delivery systems can be immunogenic and toxic. Cell-based delivery systems—using endogenous cells as natural carriers—offer low immunogenicity, low toxicity, improved biocompatibility, active tissue targeting, and the ability to cross biological barriers. This review surveys the design principles and immunotherapeutic applications of cell-based delivery systems for cancer, autoimmune diseases, and infectious diseases. --- - RBC hitchhiking: ~11.5% of drug-loaded nanoparticles carrying RBCs targeted the brain, 10× more efficient than traditional brain-targeting carriers. - Platelet-delivered aPDL1 (P-aPDL1): circulating half-life greatly increased vs free aPDL1; effectively prevented tumour recurrence and metastasis after surgery and prolonged survival in mice. - Neutrophil-carried PTX liposomes (PTX-CL/NEs): prolonged survival of glioma-bearing mice ev
Chemical Society Reviews* (as indicated by review format; exact volume/pages and DOI not included in the supplied file)2021ReviewNon-viral Gene Delivery
Yingshu Guo, Xiuping Cao, Xiaofei Zheng, Sk Jahir Abbas, Juan Li, Weihong Tan
Cancer treatment still relies heavily on chemotherapy, which causes severe damage to normal cells and systemic side effects. Safer, more selective drug delivery strategies are needed. Nanocarriers based on nucleic acids (NCNAs) are attractive because nucleic acids offer biocompatibility, low toxicity, programmable structures, controllable size, and modifiability—advantages that address limitations of cationic polymers, dendrimers, and inorganic nanoparticles. --- - DNA tetrahedron loaded with 5-fluorouracil: after 12 h co-incubation, the percentage of drug in cells was nearly 40%, demonstrating stable and efficient drug delivery. - DNA/RNA hybrid spherical nucleic acid with siRNA: rapidly absorbed by more than 60 kinds of cells; protected siRNA from enzymatic digestion and released it upon intracellular Dicer cleavage. - Se/Ru metal–organic nanoparticles + siRNA: enhanced cell uptake and promoted siRNA escape from endosomes/lysosomes, p
Michael J. Mitchell, Margaret M. Billingsley, Rebecca M. Haley, Marissa E. Wechsler, Nicholas A. Peppas, Robert Langer
Nanoparticle (NP) research has generated promising preclinical results, but clinical translation remains limited. A major barrier is the mismatch between one-size-fits-all NP designs and the heterogeneous biological barriers across patients and diseases. Precision medicine offers patient stratification, but precision therapies still face delivery barriers. This review argues that intelligent NP design can overcome these barriers and improve both general and precision therapeutic outcomes. --- - Tumour accumulation: Meta-analysis of 232 datasets found that, on average, only 0.7% of injected NP doses reach tumours. - EPR effect variability: Up to 10–15% of injected NPs accumulate at tumour sites in some studies, compared with 0.1% of free drug; however, EPR is highly heterogeneous. - Targeted NP limitation: Antibody-targeted NPs interacted with only 2% of tumour cells in one study. - iCluster system: Inhibited tumour growth by up to 95% in viv
Paula M. Cevaal, Abdalla Ali, Ewa Czuba-Wojnilowicz, Jori Symons, Sharon R. Lewin, Christina Cortez-Jugo, Frank Caruso
T cells are attractive targets for immunotherapy, cancer, HIV, autoimmunity, and inflammation, but nanoparticle delivery to T cells remains a major technological challenge due to their nonphagocytic nature and multiple physiological barriers. There is a need for rational design principles for in vivo T cell-targeting nanoparticles. --- - Barriers: Only ~2–3% of all T cells are in blood; <5% of administered nanoparticles typically reach target tissue; nanoparticles <~6 nm are renally cleared; T cells are nonphagocytic with low endocytosis rates; slow endosomal acidification in primary T cells can reduce pH-dependent cargo release. - Size rules: For receptor-mediated endocytosis (RME), optimum nanoparticle diameter ~50 nm; <200 nm preferred; >10 nm needed to avoid renal clearance; 10–100 nm ideal for lymph node delivery; <100 nm promotes escape from mononuclear phagocyte system scavenging. - Targeting outcomes: CD3-targeted PBAE/polygluta
Ian C. Miller, Ali Zamat, Lee-Kai Sun, Hathaichanok Phuengkham, Adrian M. Harris, Lena Gamboa, Jason Yang, John P. Murad, Saul J. Priceman, Gabriel A. Kwong
CAR T cell therapy for solid malignancies typically results in poor responses. Systemic administration of immunomodulatory biologics (cytokines, BiTEs) can augment T cell activity but off-target toxicity narrows the therapeutic window. A method to spatially and temporally control transgene expression by engineered T cells at tumour sites—without systemic exposure—could improve safety and efficacy. ### Thermal Switch Engineering | Parameter | Result | |---------------|------------| | Best HSE repeat number | 7 repeats (5H-7H best; 2H-4H lower response) | | Best core promoter | YB (synthetic) — ~60-fold induction.
Glioblastoma (GBM) is one of the deadliest primary adult tumours with a median survival of only 14.6 months post-diagnosis, a statistic that has changed little in two decades. While cancer immunotherapy has shown remarkable progress in other solid tumours, the blood-brain barrier (BBB) and the immune-privileged status of the central nervous system pose unique drug delivery obstacles. A comprehensive understanding of physiological, immunological ### Transport Barriers | **Barrier** | **Key Finding** | |-------------|-----------------| | BBB | Passive transport limited to <400 Da or lipid-soluble molecules; all GBM patients have tumour regions with.
Sarah J. Shepherd, Claude C. Warzecha, Sagar Yadavali, Rakan El-Mayta, Mohamad-Gabriel Alameh, Lili Wang, Drew Weissman, James M. Wilson, David Issadore, Michael J. Mitchell
Microfluidic mixing can produce precise LNPs but is limited in throughput, while bulk mixing is scalable but yields larger, heterogeneous particles with variable potency. A scalable microfluidic device is needed to produce potent RNA-LNPs across discovery and clinical scales. PMD achieved 18.4 L/h production, >100-fold higher throughput than a single microfluidic channel. - Mixing performance was uniform across 10× and 128× devices; 90% mixing channel length correlated linearly with ln(Pe).
Mandana T. Manzari, Yosi Shamay, Hiroto Kiguchi, Neal Rosen, Maurizio Scaltriti, And Daniel A. Heller
Precision medicine has transformed cancer therapy by enabling molecular profiling and optimised drug design, but clinical translation of many precision therapeutics is hindered by pharmacological limitations, including toxicities and drug resistance. Drug delivery materials can modulate a drug’s pharmacokinetics, biodistribution, and toxicity without compromising its molecular target engagement, offering a route to improve the therapeutic index. Kinase inhibitor landscape: More than 50 small-molecule protein kinase inhibitors have been FDA-approved, with the majority developed as targeted cancer therapeutics. - Dose-limiting toxicity example: In a phase I trial.
Matthew R. Aronson, Scott H. Medina, Michael J. Mitchell
Most clinically approved cancer therapies are potent and toxic small molecules limited by severe off-target toxicities and poor tumour-specific localisation. Liposomal encapsulation reduces toxicity, but reliance on passive targeting via the enhanced permeability and retention (EPR) effect leaves unresolved issues such as heterogeneous tumour accumulation. Peptide-functionalised liposomes offer an active targeting strategy for receptor-mediated. TfR-targeting T7: D-enantiomer T7 showed increased binding affinity over L-T7 and transferrin; T7-liposomes loaded with docetaxel significantly reduced tumour growth in mice. T7-quercetin liposomes increased cytotoxicity.
Self-healing polymers can repair damage and recover functionality, potentially extending the lifetime and safety of biomedical devices. Although self-healing hydrogels have been reviewed previously, papers focused specifically on their use in tissue engineering are scarce. This review summarises fabrication methods, polymers, biomedical examples, and recent progress in self-healing polymers for tissue engineering. Acylhydrazone-crosslinked nanocomposite hydrogel: self-healing efficiency 97.5%; nearly 100% cell viability. - P(BAL-co-DMSA) hydrogel: self-healing within ~5 s in air and underwater; stretchability ~4500%; complete.
Anne Vejux, Dehbia Abed-Vieillard, Khadija Hajji, Amira Zarrouk, John J. Mackrill, Shubhrima Ghosh, Thomas Nury, Aline Yamminse, Mohamed Zaibih, Wafa Mihoubi, Habiba Bouchabi, Boubker Nasser, Yael Grosjean, Gérard Lizard
7-Ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-OHC) are major auto-oxidation products of cholesterol that accumulate in cardiovascular disease, age-related macular degeneration (ARMD), neurodegenerative disorders, and inflammatory bowel diseases. While their cytotoxicity (oxidative stress, organelle dysfunction, cell death, inflammation) is well documented in cell culture, the field lacks a consolidated understanding of how these oxysterols behave in vivo and which model systems (in vitro, animal, and emerging alternatives) are most appropriate for identifying pharmacological targets and protective molecules. This review addresses that gap by systematically surveying the models and mechanisms reported to date. --- 1. Oxiappotophagy is the dominant cell death mode: 7KC and 7β-OHC simultaneously induce oxidative stress (ROS overproduction: O₂⁻, H₂O₂), apoptosis (caspase activation, PARP cleavage, DNA fragmentation), and autophagy (
Annika M. Frank, Angela H. Braun, Lea Scheib, Shivani Agarwal, Irene C. Schneider, Floriane Fusil, Severine Perian, Ugur Sahin, Frederic B. Thalheimer, Els Verhoeyen, Christian J. Buchholz
Conventional lentiviral vectors (LVs) are not selective for T cells and cannot efficiently transduce resting or minimally stimulated T lymphocytes, which limits their use for direct in vivo T-cell gene delivery. There is a need for vectors that can both target T cells specifically and activate them sufficiently to permit gene transfer without prior ex vivo activation. --- - Selectivity: CD3-LVs transduced CD3(^+) Jurkat cells but not CD3(^-) Molt4.8 cells. VSV-LV transduced HUVEC (86.74%), HepG2 (32.53%), and Nalm-6 (97.50%) cells, whereas CD3-LVs showed <0.3% transduction in these off-target cells. - Nonactivated T cells: CD3-LVs transduced freshly isolated PBMCs in the absence of cytokines or with IL-2 or IL-7/IL-15 at efficiencies similar to peak activation. VSV-LV was substantially less efficient under these conditions. - Whole blood: CD3-LVs mediated T-cell gene transfer in whole blood without additional stimuli. VCNs: TR66-LV 1.17
Xiaojing Shi, Qinqin Cheng, Tianling Hou, Menglu Han, Goar Smbatyan, Julie E. Lang, Alan L. Epstein, Heinz-Josef Lenz, Yong Zhang
Exosomes are nanosized membranous vesicles with unique properties (abundant membrane proteins, high biocompatibility, low immunogenicity) that make them attractive for therapeutic development. While exosomes have been studied as drug delivery vehicles, fewer studies have focused on engineering exosome surface proteins for cancer immunotherapy. A platform enabling genetic display of bispecific antibodies on exosomes could redirect T cells to. ### SMART-Exo Characterisation | Parameter | Result | |---------------|------------| | Size (NTA) | ~109 nm | | Surface scFv per particle | ~1,180 ± 140 molecules | | Yield | 74 μg (5.4 × 10⁹ particles) per 30 mL | |.
Julie J.-J. Tang, Alina P. Sung, Mariel J. Guglielmo, Laura N.-G., Doug Redelman, James Smith-Gagen, Diane Hudig
Monoclonal antibody anti-tumour therapies rely on NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), but patient responses vary widely. While tumour antigen escape is one cause of treatment failure, the role of inter-individual variation in NK cell serial killing capacity—the ability of a single NK cell to kill multiple target cells sequentially—has received little attention. A predictive biomarker for serial ADCC capacity. ### Killing Frequency Variability (E:T=1:4, n=24 donors) | Parameter | All Donors | Females | Males | |---------------|----------------|-------------|-----------| | KF range | 1.1 - 2.2 | 1.1 - 2.2 | 1.2 - 2.1 | | Mean.
Elana Ben-Akiva, Randall A. Meyer, Hongzhe Yu, Jonathan T. Smith, Drew M. Pardoll, Jordan J. Green
Previous red blood cell (RBC) membrane-coated nanoparticles have all been spherical, missing the physical shape component of biomimicry. Particle shape is a critical design parameter affecting biodistribution, macrophage evasion, and targeted interactions. A platform combining physical biomimicry (anisotropic shape) with chemical biomimicry (RBC membrane coating) could improve circulation time and detoxification efficacy. Macrophage uptake: RBC membrane coating reduced uptake by 30–50%; anisotropic shape reduced uptake by 30–40%; combined coating + anisotropy reduced uptake by 50–70% versus spherical uncoated particles at 4 h. - Blood.
Folic acid (FA)-mediated active targeting improves nanocarrier tumour specificity but exposes targeting ligands to the immune system, causing rapid clearance and nonspecific uptake. Existing acid-labile benzoic-imine PEG sheddable systems are insufficiently stable at physiological pH. A more stable, tumour-triggered sheddable PEG stealth is needed to protect FA in circulation and expose it at tumour sites while also promoting intracellular drug. P1 micelles: \(D_h\) = 41 nm, narrow size distribution; stable at pH 7.4. - pH-triggered destabilization: At pH 6.5, size increased from 41 nm to 80 nm after 24 h; at pH 5.0, size increased to 627 nm. -.
Yao Y, Zhou Y, Liu L, Xu Y, Chen Q, Wang Y, Wu S, Deng Y, Zhang J, Shao A.
Conventional chemotherapy and targeted therapy are limited by systemic toxicity, poor tumour targeting, and multidrug resistance (MDR). Nanoparticle-based drug delivery offers improved pharmacokinetics, biocompatibility, enhanced permeability and retention (EPR), precise targeting, and potential to overcome resistance mechanisms such as efflux transporters, defective apoptosis, and hypoxia. NPs with diameters of 10–100 nm are generally suitable for cancer therapy; <10 nm are cleared by kidneys, >100 nm are cleared by phagocytes. - PEGylation reduces opsonisation and immune clearance, prolonging.
