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.
Cm Jogdeo, K Siddhanta, A Das, L Ding, S Panja, N Kumari, D Oupický
A review of polymer-based alternatives to lipid gene delivery, including polyplexes and polymer–nucleic acid conjugates, with attention to chemical tunability and clinical translation.
CAR-T cell therapy has shown impressive success in hematological malignancies, but systemic toxicity (CRS, ICANS, on-target/off-tumor effects) and the complex, costly, individualized manufacturing process of autologous CAR-T cells hinder broader application. Universal allogeneic CAR-T cells have encountered safety concerns, with FDA halting some clinical trials. There is an urgent need for new strategies to overcome these barriers. --- - In vivo CAR-T induction with PBAE nanoparticles: Matthias Stephan's team achieved stable and transient expression of CD19-specific CAR in T cells via CAR-DNA and CAR-mRNA nanoparticles, respectively. Antitumor efficacy comparable to conventional lab-manufactured CAR-T cells without systemic toxicity. - Lentiviral in vivo CAR-T: Buchholz and colleagues induced in situ CAR-T cells in NSG mice with antitumor activity, but observed CRS and unexpected CAR-positive NK and NKT cells due to non-specific lentivi
Ann E. Metzloff, Margaret M. Billingsley, Michael J. Mitchell
mRNA vaccines have entered global use, but delivering mRNA to T cells in vivo remains challenging because T cells are non-phagocytic, reside largely in lymphoid tissues, and intravenously administered lipid nanoparticles (LNPs) tend to accumulate in the liver. There is a need for precise, scalable strategies to target mRNA to disease-specific T cells rather than all T cells, to avoid off-target inflammation and maintain self-tolerance. --- - UV-exchanged pMHCI APNs performed comparably to conventionally refolded pMHCI APNs for targeting and delivering mRNA to antigen-specific cytotoxic T cells in three mouse models. - Simultaneous targeting of three antigen-specific cytotoxic T cell populations was achieved by injecting a mixture of three UV-exchanged APNs, each carrying a different influenza A antigenic peptide. - mRNA delivery to the three antigen-specific cytotoxic T cell populations occurred at significantly higher rates compared wi
Hamideh Parhiz, Jacob S. Brenner, Priyal N. Patel, Tyler E. Papp, Hamna Shahnawaz, Qin Li, Ruiqi Shi, Marco E. Zamora, Amir Yadegari, Oscar A. Marcos-Contreras, Ambika Natesan, Norbert Pardi, Vladimir V. Shuvaev, Raisa Kiseleva, Jacob W. Myerson, Thomas Uhler, Rachel S. Riley, Xuexiang Han, Michael
Nucleoside-modified mRNA lipid nanoparticle (modmRNA-LNP) technology is clinically successful, but its behavior in pre-existing inflammatory or immune-challenged conditions is poorly characterized. This gap raises the risk of adverse effects when modmRNA-LNPs are administered to patients with ongoing inflammation. IE with LPS + modmRNA-LNP: Serum IL-6 increased 14-fold vs LPS alone and 94-fold vs modmRNA-LNP in naive mice. Liver MIP-2 increased 11-fold vs LPS alone and 52-fold vs modmRNA-LNP in naive mice. Liver MIP-2 mRNA.
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.
Martijn J.W. Evers, Wenjuan Du, Qiangbing Yang, Sander A.A. Kooijmans, Aryan Vink, Mies Van Steenbergen, Pieter Vader, Saskia C.A. De Jager, Sabine A. Fuchs, Enrico Mastrobattista, Joost P.G. Sluijter, Zhiyong Lei, Raymond Schiffelers
Modified mRNA (modRNA) is a promising cardiac regeneration therapeutic, but naked mRNA is large, negatively charged, and rapidly degraded. It is unknown whether systemically administered lipid nanoparticles (LNPs) can functionally deliver mRNA to ischemic/damaged myocardium after myocardial infarction. LNPs were <100 nm with PDI <0.2 and 95–99% mRNA encapsulation. - After ischemia-reperfusion, fluorescent LNPs accumulated in the infarcted area of the heart at 4 h and 24 h, but not in sham or control hearts. -.
Hanwen Zhang, Xuexiang Han, Mohamad-Gabriel Alameh, Sarah J. Shepherd, Marshall S. Padilla, Lulu Xue, Kamila Butowska, Drew Weissman, Michael J. Mitchell
LNPs can trigger innate immune responses and inflammation, which can suppress mRNA translation and cause adverse effects. There is a need for LNP formulations that reduce LNP-induced inflammation while maintaining or improving mRNA delivery. C9D1 and C10D0 had similar size, PDI, and >90% mRNA encapsulation; Dex substitution did not impair in vitro transfection or increase cytotoxicity. - Higher Dex substitution (C7D3, C5D5, C3D7, C0D10) reduced.
Yihua Pei, Yanjie Bao, Cristiano Sacchetti, Juthamart Brady, Kyra Gillard, Hailong Yu, Scott Roberts, Kumar Rajappan, Steven P. Tanis, Carlos G. Perez-Garcia, Padmanabh Chivukula, Priya P. Karmali
Systemic LNP delivery predominantly targets the liver, while extrahepatic delivery—especially to lung airway epithelium for diseases such as cystic fibrosis—remains challenging. DOTAP is a common cationic lipid for lung gene delivery but is racemic, pseudo-glyceryl, and slowly biodegradable. Novel readily hydrolysable DOTAP analogues are needed for safer and more effective inhaled/airway mRNA delivery. DOTAP+ and L1–L4 LNPs: <100 nm, >95% mRNA encapsulation, high mRNA purity; DOTAP− had ~71% encapsulation. - Freeze-thaw: all formulations retained size, PDI, and encapsulation within ~10% of initial values. -.
Conventional chemotherapy suffers from poor targeting and severe side effects, while synthetic nanocarriers are often cleared by the immune system and lack precise tumor targeting. Cell membrane-coated nanocarriers (CMCNs) offer a biomimetic strategy to improve biocompatibility, immune evasion, circulation time, and homotypic tumor targeting. RBC membrane-coated PLGA nanocarriers improved blood retention to 72 hours vs 15.8 hours for typical PEGylated stealth nanocarriers. - Neutrophil membrane-coated nanocarriers showed 2–3-fold higher accumulation in.
Immunotherapy has improved outcomes in cancer and infectious disease, but off-target effects, systemic toxicities, and variable efficacy remain limiting. Nanoscale engineering offers ways to manipulate immune cell functions—enhancing immunity against cancers and pathogens, controlling the site of immune response, and promoting tolerance—by tuning nanoparticle size, shape, charge, and surface chemistry. CL4H6 lipid nanoparticles silenced STAT3 and HIF-1α in tumor-associated macrophages by 37% and 48%, respectively, increased M1 markers, reduced tumor size, and altered cytokine profiles in a B16-F10 model. -.
Therapeutic nucleic acids require safe and effective in vivo delivery vectors. Most gene and cell therapies rely on ex vivo gene delivery, which is laborious, time-consuming, and costly. PBAE is a promising biodegradable synthetic cationic polymer for in vivo gene delivery due to its transfection efficiency, biodegradability, and structural tunability. This review addresses the need for a systematic understanding of PBAE components and how. PBAE half-life: 1–7 h in aqueous conditions. - Freeze-thaw stability: PBAE NPs stored at −20 °C are stable through 8 freeze/thaw cycles without significant efficacy changes. - Optimal aqueous incubation: <10 min before.
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 internalized 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 tumors remains unsupported. Solid tumors present distinct barriers—antigen heterogeneity, poor T cell trafficking/infiltration, and an immunosuppressive tumor 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 tumor 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 tumors, 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 hematological malignancies and solid tumors. --- - 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 favorable safety in early clinical trials. Tandem HER2/IL13Rα2 CARs improved anti-tumor activity and decreased antigen escape in glioblastoma models. - Toxicity reducti
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
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 tumor 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.
Kinan Alhallak, Jennifer Sun, Katherine Wasden, Nicole Guenthner, Julie O'neal, Barbara Muz, Justin King, Daniel Kohnen, Ravi Vij, Samuel Achilefu, John F. Dipersio, Abdel Kareem Azab
T-cell-based immunotherapies such as CAR-T cells and bispecific T-cell engagers (BiTEs) have shown promise but have significant limitations: (1) poor pharmacokinetics requiring continuous infusion (BiTE half-life ~2 h), and (2) single-antigen targeting leading to antigen-loss tumor escape and relapse. A modular nanoparticle platform that addresses both limitations—extending half-life and enabling multispecific targeting—could improve efficacy. ### Nanoparticle Characterization & Pharmacokinetics | Parameter | Result | |---------------|------------| | Liposome size | ~100 nm | | Half-life (non-PEGylated nanoBiTE) | ~36 h | | Half-life (PEGylated nanoBiTE) |.
Glioblastoma (GBM) is one of the deadliest primary adult tumors 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 tumors, 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 tumor 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).
Jiayu Zhou, Yishu Zhai, Jumei Xu, Tian Zhou, Lian Cen
PLGA microspheres are widely used for controlled drug release, but they often exhibit pronounced initial or mid-term burst release. A strategy is needed to finely tune drug release kinetics and suppress burst release, especially for water-soluble drugs. MSNs: Average size 119 nm; specific surface area 902.53 m²/g; pore volume 1.15 cm³/g; mean pore diameter 5.09 nm; maximum RB loading ~110 mg/g. - MSN-RB release: ~95% cumulative release within 56 h; Korsmeyer–Peppas n =.
Raza F, Zafar H, Zhang S, Kamal Z, Su J, Yuan W-E, Qiu M.
Cancer immunotherapy is limited by the immunosuppressive tumor microenvironment, patient heterogeneity, poor delivery of immunotherapeutics, and systemic immunotoxicity. Cell membrane-derived biomimetic nanoparticles may improve delivery and biodistribution, enhance targeting and immune stimulation, and overcome barriers faced by conventional nanomedicine. RBCM-coated nanoparticles improved half-life by up to 50% versus PEGylated nanoparticles and were detected in blood circulation after 72 h. - A size-reducible RBCM biomimetic system combined with.
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 optimized 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.
Polymeric nanoparticles are widely used for cancer theranostics because of their biocompatibility, biodegradability, and structural versatility, but conventional delivery still faces poor target specificity, uncontrolled release, and systemic toxicity. Stimuli-responsive polymeric nanoplatforms are proposed to exploit tumor microenvironment (TME) and external triggers to enable precise, on-demand drug/gene release at tumor sites. Representative findings highlighted in the review: - TME gradients: tumor extracellular pH is approximately 5.7–6.9 versus blood pH 7.4; intracellular GSH is 2–10 mM versus extracellular 2–10 µM; tumor ROS is about.
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 (
