Why circular RNA outperforms linear mRNA as a therapeutic modality
Circular RNA (circRNA) is a single-stranded RNA molecule with a 3’–5′ covalent linkage produced by backsplicing events, in which a downstream splice donor site joins to an upstream splice acceptor site. Because circRNAs lack 5′ caps and poly-A tails, they are resistant to standard exonuclease-mediated degradation — the primary mechanism that limits the durability of conventional linear mRNA therapeutics. This structural advantage translates directly into an extended half-life and sustained protein expression capabilities that surpass those of linear mRNA.
Three major mechanistic classes underpin therapeutic circRNA utility. First, protein-coding circRNA platforms use internal ribosome entry sites (IRES) to enable 5′-cap-independent translation, producing sustained protein output in vivo — the mechanism covered by multiple MIT and Orna Therapeutics patents using Group I intron-based permuted intron-exon (PIE) circularization. Second, miRNA sponge / competing endogenous RNA (ceRNA) modulation leverages the exonuclease resistance of circular topology to create durable competitive inhibitors of miRNA-mRNA interactions. Third, RNA decoy / regulatory blockade uses synthetic circRNAs as molecular decoys targeting RNA-binding proteins or other non-coding RNA species — the approach described in the Aarhus University EP patent.
Backsplicing is the non-canonical splicing event that produces circular RNA: a downstream splice donor site joins to an upstream splice acceptor site, creating a covalently closed loop. This is distinct from canonical linear splicing and is the defining production mechanism for endogenous and engineered circRNAs.
As the post-COVID mRNA medicine wave accelerates interest in next-generation RNA modalities, circRNA is attracting significant patent investment from leading academic spinouts and established biotech players seeking stable, low-immunogenicity alternatives for protein replacement, cancer immunotherapy, and gene regulation. According to reviews published in Nature-indexed journals, circRNA’s unique properties position it as one of the most promising post-mRNA therapeutic platforms in current development.
Circular RNA molecules lack 5′ caps and poly-A tails, rendering them resistant to standard exonuclease-mediated degradation and conferring an extended half-life and sustained protein expression advantage over conventional linear mRNA therapeutics.
The patent landscape: who owns the core circular RNA IP
Massachusetts Institute of Technology is the most prolific assignee in this dataset, with at least 7 patent records retrieved across SG (2020, 2021) and IL (2022 ×2, 2024 ×2, 2025) jurisdictions — multiple filings are active, indicating successful prosecution. MIT’s technology is commercially licensed to Orna Therapeutics and forms the core of the PIE circularization platform that underpins the majority of therapeutic circRNA development.
Orna Therapeutics holds 3 patent records in this dataset (SG ×2 pending, EP ×1 active). As a MIT spinout focusing on in vivo circRNA therapeutics targeting immune cells, its EP active filing from 2023 signals European market protection and positions the company as the primary near-term commercialization vehicle. The Aarhus University EP filing from 2018 — now inactive in this dataset — represents one of the earliest therapeutic patent filings, covering circular nucleic acids as exonuclease-resistant miRNA inhibitors and protein decoys.
In the circular RNA therapeutic patent dataset spanning 2018–2026, the dominant filing jurisdictions are IL (Israel, 7 filings), SG (Singapore, 4 filings), and EP (European Patent Office, 4 filings) — with IL and SG records typically representing PCT national phase entries originating from US priority applications.
New England Biolabs filed an EP patent active as of January 2026 covering Group II Intron reverse transcriptase rolling circle detection of circRNAs — the first tool and reagent company entry in this dataset, signaling that the analytical infrastructure ecosystem is maturing alongside therapeutic development. The Williams EP active filing from January 2025 on engineered synthetic plasmid DNA-derived circular RNA platforms represents the most recent patent priority date in this dataset and introduces independent inventor activity in the manufacturing space. The European Patent Office and WIPO PCT system are the primary international prosecution routes for this portfolio.
“MIT controls the core enabling technology. Competitors must either license this portfolio or develop non-infringing circularization chemistries — Group II intron, ribozyme-based, or ligation-based approaches.”
Explore the full circRNA patent portfolio and assignee landscape in PatSnap Eureka.
Analyse Patents with PatSnap Eureka →Four technology clusters shaping the circular RNA field
The 9 patent records in this dataset organise into four distinct technology clusters, each addressing a different layer of the circRNA therapeutic stack — from circularization chemistry and payload architecture through to manufacturing infrastructure and analytical tooling.
Cluster 1: Group I Intron PIE Circularization for Translation
This is the dominant approach among therapeutic patent filings in this dataset. Vectors are engineered with split Group I intron fragments flanking the payload sequence, enabling autocatalytic splicing that joins the RNA ends into a covalently closed loop. IRES elements — including echovirus and other IRES variants — drive cap-independent translation of the encoded protein. Key advantages claimed include improved circularization efficiency, reduced immunogenicity, and durable protein expression. MIT’s SG filing from 2021 and Orna Therapeutics’ EP active filing from 2023 are the primary records in this cluster.
Cluster 2: Multi-Payload and CAR-T Encoding Circular RNA
A sub-class of Group I intron-based circRNAs encoding multiple expression sequences separated by cleavage sites, or encoding chimeric antigen receptors (CARs) for cancer immunotherapy. Orna Therapeutics claims circRNAs with “more than one expression sequence” separated by polynucleotide-encoded cleavage sites. MIT’s IL-jurisdiction active filings from 2022 and 2024 specifically disclose CAR-encoding circRNAs with claims to in vivo immune cell expression — a critical distinction from earlier ex vivo CAR-T manufacturing approaches.
Orna Therapeutics’ EP active patent (2023) explicitly claims pharmaceutical compositions “suitable for efficient protein expression in immune cells in vivo,” marking a strategic shift from ex vivo to in vivo immune cell reprogramming with circRNA — a significant clinical development milestone.
Cluster 3: miRNA Sponge and RNA Decoy Circular RNAs
Synthetic circRNAs designed to bind and sequester microRNAs or RNA-binding proteins, preventing their activity on downstream targets. The mechanism leverages the exonuclease resistance of the circular topology to provide a durable competitive inhibitor of miRNA-mRNA interactions. The Aarhus University EP filing from 2018 is the foundational patent in this cluster, covering circular nucleic acids as exonuclease-resistant miRNA inhibitors and protein decoys. This approach has been extensively documented in the literature as a regulatory mechanism in cancer biology, as reviewed by researchers at University College London in 2020.
Cluster 4: Engineered Plasmid DNA Templates and Production Technologies
Covering the upstream manufacturing layer: engineered covalently closed plasmid DNA templates that drive circRNA production, either autonomously or with an engineered ligase. The Williams EP active filing from January 2025 introduces the concept of covalently closed synthetic plasmid DNA as a production chassis, representing a manufacturing innovation distinct from conventional linear DNA templates and potentially simplifying industrial-scale synthesis. New England Biolabs’ EP active filing from January 2026 on Group II Intron reverse transcriptase rolling circle amplification of circRNAs signals that sequencing and analytical tools are maturing alongside therapeutic development.
The Williams EP active patent filed in January 2025 introduces engineered covalently closed synthetic plasmid DNA as a circular RNA production chassis — a manufacturing approach distinct from conventional linear DNA templates and the most recent patent priority date in the circRNA dataset spanning 2018–2026.
Application domains: from CAR-T cell therapy to antigen-encoding vaccines
Circular RNA therapeutics address four primary application domains in this dataset, with oncology and cancer immunotherapy representing the largest body of both patent and literature activity.
Oncology and Cancer Immunotherapy
CircRNAs are being studied and patented as CAR-T cell activation platforms, cancer vaccine platforms, and tumor microenvironment modulators. Literature from Tsinghua University (2022) described circRNA-LNP cancer vaccines driving durable adaptive immunity in hard-to-treat malignancies. The Albert-Ludwigs-Universität Freiburg (2022) demonstrated intratumoral circular mRNA encoding cytokines for immune modulation. The Orna Therapeutics EP active patent (2023) specifically claims circRNAs “suitable for efficient protein expression in immune cells in vivo,” moving beyond ex vivo CAR-T manufacturing toward direct in vivo immune reprogramming. LNP delivery is established as the near-term clinical vehicle of choice for circRNA cancer vaccines, with Tsinghua’s 2022 work demonstrating anti-tumor efficacy in three tumor models in preclinical data.
Prophylactic and Therapeutic Vaccines
CircRNA encoding viral antigens is an active application domain. The Williams EP patent from 2025 explicitly describes fluorescence analysis of cells transfected with circRNA encoding the SARS-CoV-2 RBD sequence. Multiple Orna Therapeutics filings claim expression sequences encoding antigens generally. The Chinese Academy of Sciences literature from 2022 demonstrated a scalable co-transcriptional platform producing scarless, low-immunogenicity circRNAs with sustained expression, directly compared to linear mRNA vaccine formats — a key benchmark for next-generation vaccine development tracked by organizations including the WHO.
Gene Regulation and miRNA Therapeutics
CircRNA-based approaches to modulate the competing endogenous RNA (ceRNA) network represent a disease-agnostic application domain. Multiple literature records describe circRNA-miRNA sponge interactions relevant to cardiovascular disease, neurological disease, and infectious disease including COVID-19, HIV-1, and Ebola, extending the therapeutic scope well beyond oncology.
Protein Replacement Therapy
Protein-coding circRNAs offer an advantage over linear mRNA in conditions requiring prolonged protein expression — for example, enzyme replacement or clotting factor replacement. The MIT SG filings and IL active patents describe sustained protein production as a key claim, positioning circRNA as a durable alternative to repeat-dosing linear mRNA regimens.
Track circRNA application domain patents and clinical pipeline signals in real time with PatSnap Eureka.
Explore Full Patent Data in PatSnap Eureka →Emerging directions and strategic IP white spaces in circular RNA
Six directional signals emerge from the most recent filings and publications (2023–2026) in this dataset, with manufacturing scalability and delivery vehicle IP representing the clearest strategic white spaces for new entrants.
In vivo immune cell targeting for CAR-T and cancer immunotherapy is the most commercially advanced direction. Orna Therapeutics’ EP active patent from 2023 explicitly claims pharmaceutical compositions suitable for efficient protein expression in immune cells in vivo, moving beyond ex vivo CAR-T manufacturing toward direct in vivo immune reprogramming with circRNA. Monitoring Orna’s clinical pipeline is described as essential for competitors assessing market entry timing.
Scalable, scarless co-transcriptional circularization addresses a central manufacturing barrier. The Chinese Academy of Sciences publication from 2022 describes a self-catalyzed, co-transcriptional system producing circRNAs without foreign sequences. This approach is expected to underpin next-generation GMP-scale production. The FDA‘s evolving guidance on RNA therapeutics manufacturing will shape how these production advances translate into regulatory strategy.
Engineered closed plasmid DNA as circRNA production template — introduced in the Williams EP patent from 2025 — represents a manufacturing innovation potentially simplifying industrial-scale synthesis distinct from conventional linear DNA templates. This is identified as a relatively uncrowded area of IP compared to therapeutic payload patents.
Rolling circle detection and sequencing infrastructure is maturing. New England Biolabs’ EP active patent from January 2026 on Group II Intron reverse transcriptase-based rolling circle amplification of circRNAs signals that the analytical tools ecosystem is developing alongside therapeutics, which will accelerate clinical characterization of circRNA candidates.
Delivery vehicle IP — LNPs, exosomes, and targeted delivery to immune cells — is identified as the next major IP battleground as payload patents mature. This dataset shows circRNA payloads are advancing, but LNP formulation for circRNA and ionizable lipid chemistry for targeted immune cell delivery will become the strategic frontier.
China’s academic research output on circRNA biology is substantial, with contributors spanning Tsinghua University, Chinese Academy of Sciences, Nanjing Medical University, Sichuan University, and Southwest University. However, therapeutic patent activity in this dataset is concentrated in US and EU entities. R&D teams are advised to monitor Chinese patent filings at CNIPA, which are underrepresented in this dataset but likely significant given the volume of Chinese academic publication on circRNA-cancer biology, ceRNA networks, and computational tools.
Manufacturing scalability for circular RNA therapeutics remains an unresolved bottleneck: production purity, yield, and GMP-scale synthesis are identified as IP white spaces where companies developing novel manufacturing processes — such as co-transcriptional circularization or engineered plasmid DNA templates — may find less crowded patent landscapes than in the therapeutic payload space.
This landscape is derived from a limited set of patent and literature records retrieved across targeted searches spanning EP, SG, and IL jurisdictions alongside peer-reviewed literature from 2014–2026. It represents a snapshot of innovation signals within this dataset only and should not be interpreted as a comprehensive view of the full industry. US-jurisdiction patents and CNIPA filings are underrepresented in this dataset.