Advancements in Drug Delivery Systems

Quite a nice (and updated) review -RNA therapeutics and LNPs for extrahepatic delivery LNPs have become a cornerstone in delivering RNA therapeutics, successfully used in mRNA vaccines and gene therapies. Despite their success, LNPs' tendency to preferentially accumulate in the liver remains a critical limitation. This liver tropism hinders their effectiveness in treating diseases in other organs, such as the lungs, brain, and pancreas. 🔬 Recent research has made significant strides in re-engineering LNPs to deliver RNA to organs beyond the liver. One approach is to adjust the composition of LNP formulations, either by adding a cationic lipid (like DOTAP) or replacing the ionizable lipid's ester linkers with amide linkers. These modifications change the physicochemical properties of LNPs, influencing the biomolecular corona that forms post-administration, which ultimately determines organ-specific targeting. For instance, lung-targeted LNPs can transfect up to 65% of endothelial cells and 40% of epithelial cells in the lungs, demonstrating a potential breakthrough for treating pulmonary diseases like cystic fibrosis and pulmonary fibrosis. Spleen-specific delivery has been achieved by incorporating anionic lipids, enabling the targeting of immune cells like macrophages and T cells, essential for in vivo immunotherapy applications. Meanwhile, LNPs designed for bone marrow delivery are showing promise in treating hematopoietic disorders like sickle cell disease. 🧠 Still, delivering RNA to the brain remains a considerable challenge (you know, the usual BBB). However, promising strategies, like adding neurotransmitter-derived lipids to LNP formulations, are showing early success in crossing this barrier, paving the way for treating neurological diseases. 🎯 As we look to the future, designing LNPs that can target specific cell types and improve safety profiles is paramount. Advances in overcoming physiological barriers, such as the BBB and tissue-specific targeting, will revolutionize how we approach gene therapies for previously untreatable conditions. From organ-selective LNPs to fine-tuned biomolecular coronas, the future of RNA delivery is more promising than ever. Learn more here: https://lnkd.in/ecQjkNaq #Nanomedicine #LipidNanoparticles #GeneTherapy #RNA #BiotechInnovation #TargetedDelivery #DrugDelivery

Imagine if you could deliver a therapeutic for devastating brain diseases that crossed the blood brain barrier via an intravenous injection... The team at Icahn School of Medicine at Mount Sinai led by Yizhou Dong & Eric Nestler just demonstrated this could be possible. "We designed and synthesized a library of BCCs by covalently coupling different small molecules known for their BBB penetration abilities. Among these conjugates, BCC10 demonstrated the ability to successfully cross the BBB and deliver functional biomacromolecules through γ-secretase-mediated transcytosis. Importantly, BCC10 not only safely delivered different types of ASOs into the brain but also enhanced the efficacy of gene silencing in multiple mouse models and human brain tissues ex vivo. On the basis of the data presented, the BCC system is a highly effective system for the systemic delivery of biomacromolecules in the brain." https://rdcu.be/d1r8O

𝗕𝗿𝗲𝗮𝗸𝗶𝗻𝗴 𝗧𝗵𝗿𝗼𝘂𝗴𝗵 𝘁𝗵𝗲 𝗕𝗹𝗼𝗼𝗱–𝗕𝗿𝗮𝗶𝗻 𝗕𝗮𝗿𝗿𝗶𝗲𝗿 The current two articles provide a high-level summary of the brain shuttle technologies aiming at transporting large-molecule drugs across the blood–brain barrier (BBB) into the brain. While transferrin receptor shuttles are currently leading with massive interest from biopharma companies, other shuttle systems have been actively developed and suited for different applications: * CD98hc — A slower transporter than transferrin, potentially ideal for targeting extracellular disease pathways due to longer drug retention times. * Viral Shuttles — Adeno-associated viruses (AAVs), in particular, enable gene therapies to reach brain cells with a single dose. * Exosomes — These natural cellular messengers have natural capabilities to transport protein and nucleic acid cargoes across the BBB. 𝗥𝗲𝗮𝗹-𝗪𝗼𝗿𝗹𝗱 𝗜𝗺𝗽𝗮𝗰𝘁 Take the case of Daiza Gordon’s three sons with Hunter syndrome: a Transferrin receptor targeting peptide fused with enzyme replacing their missing IDS reached their brains, resulting in restored hearing, movement—and even prevention of symptoms in a newborn —offering renewed hope where standard treatments fell short. 𝗣𝗼𝘁𝗲𝗻𝘁𝗶𝗮𝗹 𝗮𝗽𝗽𝗹𝗶𝗰𝗮𝘁𝗶𝗼𝗻𝘀 This technology isn’t just about rare genetic diseases. Clinical pipelines are exploring brain cancer therapies, Alzheimer’s antibodies, Parkinson’s treatments, and more, aiming to deliver large biologics directly to disease sites 𝗥𝗲𝗺𝗮𝗶𝗻𝗶𝗻𝗴 𝗵𝘂𝗿𝗱𝗹𝗲𝘀 Precision targeting in the brain, long-term safety and effects, and scaling the technologies across diverse drug platforms. 👉 𝗥𝗲𝗮𝗱 𝗺𝗼𝗿𝗲:  - https://lnkd.in/eWfF6kPA - https://lnkd.in/emN4jmCc #Neuroscience #DrugDelivery #BloodBrainBarrier #Biotech #PharmaInnovation

NEW PLATFORM OVERCOMES BLOOD-BRAIN BARRIER FOR DRUG DELIVERY Researchers have developed a breakthrough system to deliver large therapeutic molecules into the brain, overcoming the challenges of the blood-brain barrier. The innovative blood-brain barrier-crossing conjugate (BCC) platform utilizes a biological process called γ-secretase-mediated transcytosis to safely transport drugs like oligonucleotides and proteins into the central nervous system via intravenous injection. In mouse models and human brain tissue, the system effectively silenced harmful genes linked to diseases such as ALS and Alzheimer’s without causing significant side effects. This advancement could revolutionize treatments for neurological and psychiatric disorders, solving a critical challenge in brain research. Key Facts: 1. The BCC system uses γ-secretase-mediated transcytosis to bypass the blood-brain barrier. 2. It successfully delivered drugs targeting harmful genes in ALS and Alzheimer’s disease. 3. The treatment was well-tolerated and effective in both mouse models and human brain tissue. Source: https://lnkd.in/gjyf7_Pb

📈Emerging New Drug Modality💡 ⚗️Peptide-drug conjugates (PDCs)🧪 Improve cancer treatment options by offering targeted therapy that enhances efficacy while minimizing systemic toxicity. Key benefits include: 1. **Tumor-Specific Targeting**: PDCs use homing peptides to selectively bind to overexpressed receptors or tumor-specific antigens, ensuring precise drug delivery to cancer cells while sparing healthy tissues. 2. **Reduced Side Effects**: By directly targeting cancer cells, PDCs minimize off-target toxicity, addressing the severe side effects of conventional chemotherapy. 3. **Improved Tumor Penetration**: Peptides are smaller (2–20 kDa) than antibodies, allowing better tissue diffusion and penetration into tumors. 4. **Versatility in Targeting Mechanisms**: PDCs can employ receptor-dependent or receptor-independent strategies, enabling treatment of tumors with heterogeneous or low receptor expression. 5. **Enhanced Payload Delivery**: PDCs can deliver highly potent cytotoxic agents that are otherwise too toxic for standalone use, transforming undruggable compounds into precision therapeutics. 6. **Modular Design**: The combination of homing peptides, linkers, and payloads allows customization for specific cancer types, improving therapeutic outcomes. 7. **Reduced Clearance and Improved Stability**: Innovations in linker chemistry ensure payload stability during circulation and efficient release at the tumor site, overcoming challenges like premature cleavage and rapid renal clearance. 8. **Potential for Resistant Cancers**: PDCs can address unmet needs in oncology by targeting resistant or refractory cancers, as demonstrated by candidates like CBX-12. These advancements position PDCs as a promising frontier in precision oncology, complementing or surpassing current therapies like antibody-drug conjugates (ADCs). https://lnkd.in/g_4Rm47G

Do you work with #mRNA #DrugDelivery using #LNPs? And looking for ways to expedite your research using #MachineLeanining? Then this exciting new publication in Advanced Healthcare Materials is a must read. The article “Advancing Cellular‐Specific Delivery: Machine Learning Insights into Lipid Nanoparticles Design and Cellular Tropism” showcases integration of design of experiments (DoE), high-throughput screening, and machine learning to tailor #LipidNanoparticle formulations for immune cell targeting. The team (Belal Hanafy, Michael Munson, Ramesh Soundararajan, Sara Pereira, Audrey Gallud, Sajib Md Sanaullah, Gianluca Carlesso, and Mariarosa Mazza) developed predictive models that not only optimize LNP composition but also demonstrate in vivo delivery to immune cells with reduced liver uptake. A great example of how data-driven innovation can accelerate the development of next-generation delivery systems for mRNA and other nucleic acid therapeutics and a very worthwhile read. Congratulations to AstraZeneca #AdvancedDrugDelivery team members and collaborators on this impactful contribution to the field of drug delivery! Read more here: https://lnkd.in/eMvZQUYP