Strategies to deliver RNA nanomedicine directly into target cells/ tissues Tissue/cell-specific delivery

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• Advancing regenerative medicine with RNA nanotechnology for chronic and end organ diseases (2026) · Communications Medicine · doi

  Strategies to deliver RNA nanomedicine directly into target cells/ tissues Tissue/cell-specific delivery. Since most nanoparticles are system- atically administered, an urgent challenge lies in the specific delivery of the circulated mRNA molecules to the site of interest. They are also highly prone to nuclease degradation and, therefore, susceptible to degradation prior to reaching the organ of interest, further affecting therapeutic efficacy. Moreover, the mRNA may require cellular penetration for gene editing; hence, strategies for cytosolic delivery also need to be considered51,52. To overcome these obstacles, different surface ligands and careful design of nanoparticles are necessary for a successful targeted and efficacious therapy. Recently, for lung targeting, Qui et al. reported a novel PEGylated KL4 peptide (PEG12KL4) that acts as a pulmonary surfactant protein B (SP-B) mimic and can be conjugated on nanoparticle surfaces for effective delivery to the lung epithelial cells53,54. Additionally, researchers have also discovered that although the majority of LNPs are made of ionizable lipids, utilizing ionizable lipids with low pKa and unsaturated hydrocarbons and/or 0.5% PEG during LNP formulation elicits greater transfection efficiency in the retinal pigment epithelium (RPE) cells of the eye following subretinal injections55. Similarly, while most lipid nanoparticles accumulate in the liver, it is crucial to identify the liver cells of interest more specifically for therapeutic targeting and to avoid any off-target distribution and toxicity. Considering this, Han et al. have recently developed an anisamide ligand-tethered lipi- doid (AA-T3A-C12) as a high-affinity ligand for the overexpressed sigma receptors on activated fibroblasts and HSCs50. These novel LNPs showed greater RNA delivery to activated fibroblasts in the liver compared to the current FDA-approved MC3 ionizable lipid. Also, 2-fold fibroblast uptake and decreased liver fibrosis were evident using the AA-T3A-C12 formulated LNPs with heat shock protein 47 siRNA as the therapeutic target for liver fibrosis50. Alternatively, researchers have discovered that apolipoprotein E (ApoE) and N-acetylgalactosamine (GalNAc) can direct the nanoparticle uptake specifically to hepatocytes through the lipoprotein (LDLR) and asialoglycoprotein (ASGPR) receptors, respectively46,56,57. Hepatocyte tar- geting is crucial for several diseases, including hereditary amyloidosis that is currently being treated by GalNAc-mediated hepatocyte targeting LNPs – Onpattro. Subsequently, RNA nanomedicine has also shown promise in cardiac regeneration for myocardial infarction and gene modulation in inherited cardiac diseases; however, insufficient RNA delivery to the cardiac tissue is often an obstacle. Researchers have been studying different approaches to maximize cardiac tissue delivery by optimizing the various excipients used in LNP formulation development. In a recent study, a positively charged ionizable lipid C1

  generalfuture work
  Keywords: delivery liver cells speci lnps ionizable cardiac target tissue nanoparticles interest therapeutic targeting researchers lipid
• Translational Advances in Lipid Nanoparticle-Mediated Nucleic Acid Therapeutics for Cancer Immunotherapy: Overcoming Resistance and Engineering Immunity (2026) · YMER Digital · doi

  Synthesis of Findings The advent of lipid nanoparticle (LNP) technology has catalyzed a profound paradigm shift in modern medicine, acting as the critical translational bridge between fundamental molecular VOLUME 25 : ISSUE 04 (April) - 2026 Page No:364. YMER || ISSN : 0044-0477 https://ymerdigital.eu/ biology and clinical oncology. Historically, the clinical utility of nucleic acid therapeutics was severely bottlenecked by their inherent physicochemical vulnerabilities, including rapid enzymatic degradation by ubiquitous nucleases, unfavorable electrostatic properties preventing cellular uptake, and endosomal entrapment. By engineering a sophisticated, multi- component core-shell architecture integrating pH-responsive ionizable lipids, structural phospholipids, cholesterol, and stealth polymers LNPs have successfully overcome these formidable biological barriers. In the context of cancer immunotherapy, this platform has evolved from a simple protective carrier into an active, programmable immunomodulator. Today, LNPs uniquely facilitate the rapid translation of genomic data into precision therapeutics, enabling the in vivo generation of chimeric antigen receptor (CAR) T-cells, the targeted delivery of patient-specific neoantigen vaccines, and the spatiotemporal remodeling of the highly immunosuppressive tumor microenvironment (TME). The Road Ahead: Advancing RNA Architectures While conventional linear mRNA-LNP platforms have achieved landmark clinical validations, their inherently transient expression kinetics mandate repeated dosing regimens, which can exacerbate cumulative toxicities, induce immune exhaustion, and increase patient burden. To achieve durable anti-tumor immunity and expand the therapeutic window, the field must aggressively pivot toward advanced, next generation RNA formats, most notably circular RNA (circRNA) and self-amplifying RNA (saRNA). Circular RNA (circRNA): By utilizing a covalently closed-loop structure that lacks free 5' and 3' termini, circRNA is rendered highly resistant to exonuclease mediated degradation. When formulated within LNPs, this structural stability translates to exponentially prolonged intracellular half-lives, yielding superior and sustained antigen or CAR expression for weeks rather than days, all without the risks of genomic integration. Self-Amplifying RNA (saRNA): By incorporating viral replication machinery (e.g., alphavirus RNA-dependent RNA polymerase), saRNA constructs actively amplify the therapeutic transcript within the host cell cytosol. This self-replication mechanism significantly amplifies translational yield, exerting a profound dose sparing effect that requires 10- to 100-fold lower payload concentrations compared to conventional linear mRNA. Consequently, saRNA-LNPs mitigate the systemic reactogenicity and manufacturing costs associated with high lipid-to-RNA ratios while driving potent, long lasting T-cell responses. A Call for Multidisciplinary Collaboration The future of LNP-mediated cancer immunotherapy is intrinsically tied to our ability to orchestrate complex, multi-scale biological interventions. Overcoming the remaining clinical bottlenecks such as the physical barriers of desmoplastic solid tumors, the accelerated blood clearance (ABC) phenomenon, and the necessity for ultra-cold chain logistics demands unprecedented, multidisciplinary collaboration. The integration of artificial intelligence and machine learning is required to accelerate neoantigen discovery and automate the inverse design of optimized, organ-tropic lipid chemistries. Concurrently, materials scientists, immunologists, and clinical oncologists must unite to engineer stimuli-responsive and VOLUME 25 : ISSUE 04 (April) - 2026 Page No:365. YMER || ISSN : 0044-0477 https://ymerdigital.eu/ lyophilizable nanocarriers that bypass cold-chain dependencies. Through this synergistic convergence of scientific disciplines, the ultimate vision of precision oncology can be realized: the development of potent, "off-the-shelf", and universally accessible cancer immunotherapies that provide curative outcomes for patients worldwide.

  generalfuture work
  Keywords: clinical lnps sarna lipid cancer circrna self profound translational volume issue april page ymer issn
• Targeted delivery platforms for in vivo immune cell engineering: emerging strategies for cancer immunotherapy (2026) · Frontiers in Pharmacology · doi

  However, with the rapid progress of targeted delivery technologies, in vivo immune cell engineering moves from proof- of-concept experiments to the clinic. While existing adoptive cell therapies provide sufficient therapeutic outcomes, the ability to edit the immune cells right inside the body holds promises to make cell therapy manufacturing more efficient, cheaper, and more accessible (Gao B. et al., 2026). Still, there are numerous scientific and safety considerations which should be resolved before implementing targeted in vivo delivery technologies in clinical routine. 7.1 Current clinical studies While most targeted in vivo immune cell engineering methods are still in preclinical studies, the progress of the field is such that its technologies become closer to being tested in clinical trials. The success of non-viral nucleic acid delivery platforms based on liposomes, such as mRNA in COVID-19 vaccines, proves the safety, scalability, and clinical viability of those approaches, providing good background for using the same technology in cancer immunotherapy. Further progress made by preclinical research shows that antibody-targeted LNPs can specifically deliver mRNA, DNA, siRNA, or gene-editing cargo to the immune cells, thus reprogramming them in vivo without ex vivo manufacturing (Billingsley et al., 2024). Recently, the field entered an important phase of clinical translation. Particularly, the targeted non-viral in vivo platform for BCMA-specific CAR-T generation–ESO-T01 – has become the first of its kind to enter early clinical evaluation in relapsed or refractory multiple myeloma (Gao Y. et al., 2026). This achievement marks an important point for translating targeted immune-cell engineering into clinical practice and provides the first chance to test the safety and therapeutic value of in vivo CAR-T production in humans. Besides the CAR-T therapies, therapeutic platforms utilizing several clinical-stage RNA nanoparticles target immune microenvironment, delivering mRNA, siRNA, immune agonists, or gene editing components to enhance antigen presentation, reverse immune suppression, T-cell activation, and increase the effectiveness of immune checkpoint inhibitors. Despite most of in early clinical development, those technologies are still improved clinical safety promising preclinical efficacy and profiles show that targeted non-viral delivery platforms are starting to become a viable alternative to traditional viral vector- or ex vivo manufacturing-based cell therapies. in vivo modulation of tumor 7.2 Safety and regulatory challenges cause immune anti-drug responses upon Despite the promising therapeutic potential, several biological,

  generalfuture work
  Keywords: immune clinical vivo targeted cell safety delivery technologies therapeutic viral progress engineering therapies manufacturing still

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