Aug 2026· Bioengineering & Translational Medicine· 0 citations· 36 references
Medicine
TL;DR
New insights into the precision treatment of endometrial cancer are provided by developing engineered, multifunctional, exosome-based therapeutic drugs that combine mechanism precision and translational feasibility in tumor treatment.
Abstract
Abstract Therapeutic challenges in endometrial carcinoma (EC) arise from the limited efficacy and toxicity of current treatments. Although exosome‐based RNA interference shows promise, its clinical translation is hindered by inefficient cargo loading, low yields, and poor tumor targeting. We have engineered an exosome platform (cRGD‐ExoM) that integrates the following innovations: Firstly, RNA motifs enable the enrichment of shRNA loading by over 80‐fold for targeting of ferroptosis regulators (glutathione peroxidase 4/ferroptosis suppressor protein 1/ferritin heavy chain [GPX4/FSP1/FTH]). Secondly, Rab4 silencing amplifies exosome biogenesis via dysregulated endosomal recycling, enhancing tumor cell uptake by impairing endosome maturation—a dual‐action mechanism that boosts both production and delivery. Thirdly, cRGD peptides confer αvβ3‐integrin‐specific targeting. cRGD‐ExoM induces potent ferroptosis by increasing lipid peroxidation and downregulating GPX4/FSP1/FTH, significantly suppressing EC tumor growth in vivo without causing systemic toxicity. The platform's modular design allows for spatiotemporal control of loading, production, and targeting, demonstrating its scalability. This study provides new insights into the precision treatment of endometrial cancer by developing engineered, multifunctional, exosome‐based therapeutic drugs that combine mechanism precision and translational feasibility in tumor treatment.
ABSTRACT A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood–brain barrier (BBB) while achieving cell‐type‐specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron‐targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein‐derived peptide, the system enables receptor‐mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor‐interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau‐associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age‐defined, cell‐derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.
Chi Zhang, Jiaqi Zhang, Yuzhi Wang et al.· Advancement of science· 0 citations
ABSTRACT Acquired paclitaxel (PTX) resistance remains a major obstacle in triple‐negative breast cancer (TNBC) treatment. This study investigated TIPE1's role in regulating autophagy and PTX sensitivity and developed ROS‐responsive TIPE1 mRNA‐loaded nanoparticles (TIPE1m NPs) as a therapeutic strategy. PTX‐resistant TNBC cell lines were established, and integrated transcriptomic and proteomic analyses were performed. TIPE1 was downregulated in resistant cells, while higher TNFAIP8L1 expression in public breast cancer cohorts was associated with better survival and improved PTX response. Mechanistically, TIPE1 overexpression was associated with ubiquitination‐related reduction in the stability of the small GTPase RAB7A, leading to impaired autophagic flux, increased ROS accumulation, and enhanced PTX‐induced apoptosis. Conversely, TIPE1 knockdown stabilized RAB7A, enhanced autophagy, and increased PTX tolerance. ROS‐responsive TIPE1m NPs were constructed to restore TIPE1 expression in resistant cells. TIPE1m NPs suppressed autophagy, increased ROS, and enhanced PTX‐induced apoptosis in vitro. In PTX‐resistant xenografts, combined TIPE1m NPs and PTX treatment suppressed tumor growth without obvious systemic toxicity. These findings identify the TIPE1–RAB7A–autophagy axis as a potential therapeutic target and support TIPE1 mRNA delivery as a strategy to overcome PTX resistance in TNBC.
Wei Hu, Qishuai Chen, Yan Ma et al.· Advancement of science· 0 citations
Non-melanoma skin cancer squamous cell carcinoma (NMSC-SCC) represents a growing clinical burden, particularly among coastal populations with prolonged UV exposure. Despite available surgical and systemic therapies, current approaches lack molecular specificity and multitarget efficacy. Long non-coding RNAs (lncRNAs) HOTAIR and ANRIL have been identified as oncogenic drivers in SCC through epigenetic silencing of tumor suppressor genes via Polycomb Repressive Complex 2 (PRC2) and activation of the Hedgehog (Hh) signaling pathway. Concurrently, miRNA-125b functions as a tumor suppressor by downregulating BCL-2 and BMI1, both of which are promoted by HOTAIR and ANRIL overexpression. Antisense oligonucleotides (ASOs) offer a promising RNA-targeting strategy capable of degrading lncRNA transcripts via RNase H-mediated cleavage and sterically blocking translational machinery. However, effective intracellular delivery remains a major challenge. This review proposes a novel delivery platform, PEG-modified alginate-chitosan nanoparticles (PEG-CANPs) derived from Macrocystis pyrifera brown algae, to encapsulate ASOs targeting HOTAIR and ANRIL, while synergistically modulating miRNA-125b expression. The ionotropic gelation method enables efficient encapsulation with high stability under acidic conditions, supporting transdermal delivery to skin cancer lesions. Evidence from prior studies demonstrates that ASO-modified CANPs effectively suppress BCL-2 and c-MET in breast cancer models, supporting their translational potential. This review synthesizes current molecular evidence and proposes a mechanistic framework for the synergistic multi-target approach in NMSC-SCC. Further preclinical studies are warranted to validate efficacy and safety.
G. Pranowo, Gilang Prayoga Putra Permana, Siti Aminah Tri Susila Estri· PROSIDING DISEMINASI ILMIAH...· 0 citations
Aim: Acute myeloid leukemia (AML) remains a highly aggressive hematologic malignancy with limited therapeutic options. This study aimed to elucidate how reticulocalbin-1 (RCN1) regulates mitochondrial DNA (mtDNA)-mediated innate immune signaling in AML and to evaluate the therapeutic potential of extracellular vesicle (EV)-mediated small interfering RNA (siRNA) delivery targeting RCN1.
Methods: Stable RCN1 knockdown was achieved in AML cells using lentiviral delivery of short hairpin RNA. Mitochondrial transcription factor A (TFAM) expression, mtDNA leakage, and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-type I interferon pathway were analyzed by immunoblotting and quantitative polymerase chain reaction. Protein interactions were assessed by co-immunoprecipitation, proximity ligation assay, and immunofluorescence. TFAM rescue experiments were performed to evaluate its contribution to the downstream effects of RCN1 knockdown. For translational evaluation, EVs were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, and marker protein detection, followed by loading with siRNA targeting RCN1. Therapeutic efficacy and safety were assessed in an AML xenograft mouse model.
Results: RCN1 knockdown reduced TFAM expression, leading to cytoplasmic mtDNA accumulation and activation of the cGAS-STING-type I interferon signaling pathway. Restoration of TFAM expression attenuated mtDNA leakage and downstream signaling. EV-delivered siRCN1 effectively suppressed tumor growth in vivo without detectable toxicity.
Conclusion: RCN1 silencing destabilizes mtDNA integrity and activates innate immune signaling in AML. EV-based delivery of siRCN1 may represent a promising and potentially safe therapeutic strategy for AML.
Huan Chen, N. An, Linlin Yang et al.· Extracellular Vesicles and C...· 0 citations
Inducing ferroptosis in hepatocellular carcinoma (HCC) cells represents an important therapeutic strategy, but intrinsic resistance mechanisms often limit efficacy. Therefore, elucidating the mechanisms underlying ferroptosis resistance in HCC cells can facilitate the development of effective therapeutic strategies. Here, we performed genome-wide CRISPR/Cas9 library screens to identify TRIM27 as a key determinant of ferroptosis resistance. TRIM27 knockdown markedly potentiated erastin-induced ferroptosis in HCC cells, whereas TRIM27 overexpression suppressed the expression of fatty-acid metabolic enzymes including ACSL4 and reduced oxidized lipid accumulation. Mechanistically, TRIM27 directly binds with ACSL4 and promotes its K48-linked ubiquitination and degradation, thereby attenuating ferroptosis in HCC cells. Furthermore, we developed TRIM27-Cas9-loaded EVs with robust editing efficiency. These engineered EVs were readily internalized by HCC cells and preferentially accumulated in the liver. Functionally, TRIM27-Cas9-loaded EVs inhibited HCC cell proliferation by enhancing ACSL4-mediated ferroptosis and significantly improved the anti-tumor efficacy of anti-PD-1 therapy in HCC. Collectively, our findings suggest that TRIM27 confers ferroptosis resistance via facilitating K48-linked ubiquitination and subsequent proteasomal degradation of ACSL4. TRIM27-Cas9-loaded EVs restore cellular sensitivity to ferroptosis, inhibit HCC proliferation, and sensitize HCC lesions to anti-PD-1 immunotherapy.
Jie Wen, Zhihui Wang, Zhirui Zeng et al.· Cell Death and Differentiati...· 0 citations
Lipid nanoparticles (LNPs) are state‐of‐the‐art siRNA carriers but are limited by modest RNA loading, inefficient endosomal escape, and short‐lived silencing due to burst release at escape. To overcome these constraints, we developed lipid‐layered core RNA‐assembled nanomodules (L‐CRAMs) that couple a self‐assembled RNA core with fusogenic lipids to enable sustained, high‐capacity siRNA delivery. L‐CRAMs release siRNA gradually, exhibit fusion‐mediated intracellular delivery with limited endo‐lysosomal sequestration, and produce robust silencing across single and multiplexed targets in vitro. Compared with MC3‐LNPs, L‐CRAMs prolonged intracellular gene silencing. Following systemic administration in mice, L‐CRAMs induced potent, durable suppression of the clinically relevant liver gene APOC3, accompanied by reductions in serum triglycerides (TG) and triglyceride‐rich lipoproteins (TRL). By integrating ultra‐high RNA payloads, fusogenic uptake, and programmable multi‐gene targeting, L‐CRAMs provide a versatile, long‐acting RNA interference platform that addresses key limitations of existing LNP systems and advances therapeutic RNA delivery.
S. Moon, Iksoo Jang, Taehyeon Kim et al.· Advanced Functional Material...· 0 citations
Related blog posts
MIT News · Artificial Intelligence· news.mit.eduAug 27, 2026
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
