mRNA Therapies

We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort.

Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19⁺ cells were associated with a positive humoral response, whereas a higher CD4⁺/CD8⁺ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

Abstract Messenger ribonucleic acid (mRNA) vaccines are a relatively new class of vaccines that have shown great promise in the immunotherapy of a wide variety of infectious diseases and cancer. In the past 2 years, SARS‐CoV‐2 mRNA vaccines have contributed tremendously against SARS‐CoV2, which has prompted the arrival of the mRNA vaccine research boom, especially in the research of cancer vaccines. Compared with conventional cancer vaccines, mRNA vaccines have significant advantages, including efficient production of protective immune responses, relatively low side effects and lower cost of acquisition. In this review, we elaborated on the development of cancer vaccines and mRNA cancer vaccines, as well as the potential biological mechanisms of mRNA cancer vaccines and the latest progress in various tumour treatments, and discussed the challenges and future directions for the field.

Direct vaccination with mRNA encoding tumor antigens is a novel and promising approach in cancer immunotherapy. CureVac's mRNA vaccines contain free and protamine-complexed mRNA. Such two-component mRNA vaccines support both antigen expression and immune stimulation. These self-adjuvanting RNA vaccines, administered intradermally without any additional adjuvant, induce a comprehensive balanced immune response, comprising antigen specific CD4+ T cells, CD8+ T cells and B cells. The balanced immune response results in a strong anti-tumor effect and complete protection against antigen positive tumor cells. This tumor inhibition elicited by mRNA vaccines is a result of the concerted action of different players. After just two intradermal vaccinations, we observe multiple changes at the tumor site, including the up-regulation of many genes connected to T and natural killer cell activation, as well as genes responsible for improved infiltration of immune cells into the tumor via chemotaxis. The two-component mRNA vaccines induce a very fast and boostable immune response. Therefore, the vaccination schedules can be adjusted to suit the clinical situation. Moreover, by combining the mRNA vaccines with therapies in clinical use (chemotherapy or anti-CTLA-4 antibody therapy), an even more effective anti-tumor response can be elicited. The first clinical data obtained from two separate Phase I/IIa trials conducted in PCA (prostate cancer) and NSCLC (non-small cell lung carcinoma) patients have shown that the two-component mRNA vaccines are safe, well tolerated and highly immunogenic in humans.

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity, especially in genetic alteration and microenvironment. Conventional therapeutic strategies for pancreatic cancer usually suffer resistance, highlighting the necessity for personalized precise treatment. Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting, minimal nonspecific effects, broad therapeutic window, low toxicity, and induction of persistent immunological memory. Multiple conventional vaccines based on the cells, microorganisms, exosomes, proteins, peptides, or DNA against pancreatic cancer have been developed; however, their overall efficacy remains unsatisfactory. Compared with these vaccine modalities, messager RNA (mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment, and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer. This review summarizes the current progress on pancreatic cancer vaccines, highlights the superiority of mRNA vaccines over other conventional vaccines, and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.

Among the few available mRNA delivery vehicles, lipid nanoparticles (LNPs) are the most clinically advanced but they require cumbersome four components and suffer from inflammation‐related side effects that should be minimized for safety. Yet, a certain level of proinflammatory responses and innate immune activation are required to evoke T‐cell immunity for mRNA cancer vaccination. To address these issues and develop potent yet low‐inflammatory mRNA cancer vaccine vectors, a series of alternating copolymers “PHTA” featured with ortho‐hydroxy tertiary amine (HTA) repeating units for mRNA delivery is synthesized, which can play triple roles of condensing mRNA, enhancing the polymeric nanoparticle (PNP) stability, and prolonging circulation time. Unlike LNPs exhibiting high levels of inflammation, the PHTA‐based PNPs show negligible inflammatory side effects in vivo. Importantly, the top candidate PHTA‐C18 enables successful mRNA cancer vaccine delivery in vivo and leads to a robust CD8+ T cell mediated antitumor cellular immunity. Such PHTA‐based integrated PNP provides a potential approach for establishing mRNA cancer vaccines with good inflammatory safety profiles.

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8^+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

In recent years, the use of messenger RNA (mRNA) in the fields of gene therapy, immunotherapy, and stem cell biomedicine has received extensive attention. With the development of scientific technology, mRNA applications for tumor treatment have matured. Since the SARS-CoV-2 infection outbreak in 2019, the development of engineered mRNA and mRNA vaccines has accelerated rapidly. mRNA is easy to produce, scalable, modifiable, and not integrated into the host genome, showing tremendous potential for cancer gene therapy and immunotherapy when used in combination with traditional strategies. The core mechanism of mRNA therapy is vehicle-based delivery of in vitro transcribed mRNA (IVT mRNA), which is large, negatively charged, and easily degradable, into the cytoplasm and subsequent expression of the corresponding proteins. However, effectively delivering mRNA into cells and successfully activating the immune response are the keys to the clinical transformation of mRNA therapy. In this review, we focus on nonviral nanodelivery systems of mRNA vaccines used for cancer gene therapy and immunotherapy.

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by the pandemic. No specific regulations existed at the time they were marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that the pandemic emergency has passed, it is time to consider the safety issues associated with this rapid approval. The mode of action of COVID-19 mRNA vaccines should classify them as gene therapy products (GTPs), but they have been excluded by regulatory agencies. Some of the tests they have undergone as vaccines have produced non-compliant results in terms of purity, quality and batch homogeneity. The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues. Post-marketing studies have shown that mRNA passes into breast milk and could have adverse effects on breast-fed babies. Long-term expression, integration into the genome, transmission to the germline, passage into sperm, embryo/fetal and perinatal toxicity, genotoxicity and tumorigenicity should be studied in light of the adverse events reported in pharmacovigilance databases. The potential horizontal transmission (i.e., shedding) should also have been assessed. In-depth vaccinovigilance should be carried out. We would expect these controls to be required for future mRNA vaccines developed outside the context of a pandemic.

Dear Editor, mRNA-based therapeutics have gained the public ’ s attention in the post-COVID era. The application of mRNA vaccines is not limited to infectious diseases but extends to broader areas, such as cancers and rare genetic disorders. 1 – 3 This fi rst-in-human study demonstrated the safety and preliminary ef fi cacy of mRNA vaccines targeting multiple neoantigens in 13 patients with advanced melanoma. 4 The vaccines signi fi cantly reduced recurrent metastatic events, improving progression-free survival. Steven Rosenberg ’ s group later reported that mRNA vaccines could generate mutation-speci fi c T-cell responses against predicted neoepitopes in 4 patients with metastatic gastrointestinal cancer. 5 However, no objective clinical responses were observed. Therefore, whether the application of mRNA vaccines can be expanded to cold tumors such as gastrointestinal tumors remains to be addressed. Recently, the ef fi cacy of personalized mRNA vaccines targeting multiple neoantigens in combination with programmed death 1 ligand (PD-L1) inhibitors and mFOLFIRINOX (a modi fi ed version of a four-drug chemotherapy regimen) in delaying recurrence in pancreatic cancer patients after surgical resection was reported. 6 The median recurrence-free survival was not yet reached for vaccine responders (50% of the patients enrolled), compared with an average of 13.4 months for nonresponders. Similarly, personalized mRNA vaccines with up to 34 neoantigens plus the PD-1 inhibitor pembrolizumab slowed recurrence in postsurgical patients with melanoma in the phase IIb KEYNOTE-942 trial. 7 These early trials suggested that utilizing personalized vaccines to cover multiple neoantigens in the postsurgical setting with a low tumor load is a practical strategy for mRNA therapeutics. Whether a tumor vaccine can be used in late-stage cancer

TPS9107 Background: Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine can enhance the activity of checkpoint blockade. The vaccine BI 1361849 (comprising 6 mRNAs encoding for selected tumor-associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1) is combined with 1 or 2 checkpoint inhibitors (durva [anti-PD-L1] ± treme [anti-CTLA-4]). Methods: This ongoing Phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in NSCLC patients. In arm A, an initial dose-evaluation phase follows a 3+3 design to determine the dose of durva (1500 or 750 mg) to be given with the vaccine. Arm B uses the durva dose from Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n = 10), which receives the checkpoint inhibitors only. Study treatment is administered over 12 (28-day) cycles. Durva (x 12 doses) and treme (x 4 doses) are administered intravenously every 28 days. The vaccine is administered on 1 to 3 days over each of the 12 cycles using a device that provides a needle-free intradermal administration. The primary endpoint is safety/tolerability per CTCAE, including dose-limiting toxicity during dose evaluation. Secondary endpoints are progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20Dec2017. Clinical trial information: NCT03164772.

Abstract Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). BI 1361849 (formerly CV9202) is a cancer vaccine comprising 6 mRNA constituents, each of which encodes for one of the non-small cell lung cancer (NSCLC) associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2, and MAGE-C1. Durvalumab (durva) is a checkpoint inhibitor that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 (PD-1). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. Tremelimumab (treme) is an anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) blocking antibody. Targeting both the CTLA-4 and PD-1 checkpoint pathways provides the potential for additive or synergistic effects. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine, BI 1361849, can enhance the activity of checkpoint blockade. This ongoing phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in patients with NSCLC. In Arm A, an initial dose evaluation phase follows a 3+3 design to confirm the dose of durva (full dose 1500 mg or de-escalated 750 mg, if needed) to be given with the vaccine. Arm B uses the dose established in Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n=10), in which patients receive the checkpoint inhibitor(s) only. Study treatment is administered over 12 cycles (28 days each). Durva (x 12 doses) and treme (x 4 doses, Arm B only) are administered intravenously every 28 days. The vaccine is administered as a total of 14 doses (of the 6 components) during the 12 cycles, using a device that provides a needle-free intradermal administration. The primary endpoint is assessment of safety and tolerability, including evaluation of dose-limiting toxicities. Secondary endpoints include progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST 1.1 and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20 December 2017. As of 27 June 2018, 2 patients are enrolled; enrollment is ongoing. Citation Format: Joshua Sabari, Kristen Aufiero Ramirez, Paul Schwarzenberger, Toni Ricciardi, Mary Macri, Aileen Ryan, Ralph Venhaus. Phase 1/2 study of mRNA vaccine therapy + durvalumab (durva) ± tremelimumab (treme) in patients with metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B209.

Summary Background mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidots®, for delivering unmodified mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumour responses. Methods We evaluated whether NLC OVA mRNA complexes activate dendritic cells (DCs) in vitro and identified the involved signalling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in B16-OVA and E.G7-OVA cold tumour-bearing C57Bl6 female mice as well as its synergy effect with an anti-PD-1 therapy by following the tumour growth and performing immunophenotyping of innate and adaptive immune cells. The intratumoral vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumour cells. Findings Our vaccine activates DCs in vitro through the TLR4/8 and ROS signalling pathways and induces specific T cell activation while exhibits significant preventive and therapeutic antitumour efficacy in vivo. A profound intratumoral remodelling of the innate and adaptive immunity in association with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction were observed in immunised mice. The combination of vaccine and anti-PD-1 therapy improves the rates of complete responses and memory immune responses compared to monotherapies. Interpretation Lipidots® are effective platform for the development of vaccines against cancer based on mRNA delivery. Their combination with immune checkpoint blockers could counter tumour resistance and promote long-term antitumour immunity. Funding This work was supported by 10.13039/501100015760Inserm Transfert, 10.13039/501100010115la Région Auvergne Rhône Alpes, 10.13039/100008656FINOVI, and the French Ministry of Higher Education, research and innovation (LipiVAC, COROL project, funding reference N° 2102992411).

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor‐associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co‐deliver a tumor‐associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene‐WT1 mRNA to the core tumor region using photo‐driven and hypoxia‐driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo‐immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

Breast cancer represents the most prevalent cancer among women globally, constituting approximately 30% of newly diagnosed female malignancies and serving as the second leading cause of cancer-related mortality, accounting for 11.6% of deaths. Despite notable advancements in survival rates and quality of life for breast cancer patients over recent decades—achieved through interventions such as surgery, chemotherapy, radiotherapy, and endocrine therapy—there remains an urgent need for novel therapeutic strategies. This necessity arises from challenges associated with recurrence, metastasis, and drug resistance. The COVID-19 pandemic has accelerated the development of Messenger RNA (mRNA) vaccines at an unprecedented pace, and as a novel form of precision immunotherapy, mRNA vaccines are increasingly being recognized for their potential in cancer treatment. mRNA vaccines efficiently produce antigens within the cytoplasm, specifically activating the immune system to target tumor cells while minimizing the risk of T-cell tolerance. Therefore, mRNA vaccines have emerged as a promising approach in cancer immunotherapy. This review systematically examines the principles, mechanisms, advantages, key targets, and recent progress in mRNA vaccine therapy for breast cancer. Furthermore, it discusses current challenges and suggests potential directions for future research.

Atherosclerosis, a major cause of cardiovascular disease (CVD), involves plaque buildup in arteries driven by inflammation, endothelial dysfunction, and lipid metabolism disturbances. Current therapies aim to reduce cholesterol through statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, prevent blood clots with antiplatelet drugs like aspirin, and control inflammation, alongside lifestyle modifications. However, these approaches often fall short due to patient non-compliance and residual risks. This review explores emerging mRNA vaccine strategies targeting the complex mechanisms of atherosclerosis. These vaccines could produce therapeutic proteins to modulate inflammation by encoding sequences that inhibit pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), stabilizing plaques. Key targets include interleukin-10 (IL-10) for plaque stability, PCSK9 for cholesterol regulation, and vascular endothelial growth factor (VEGF) for endothelial repair. Addressing these unmet needs, mRNA-based approaches offer the potential for more effective and personalized treatments for atherosclerosis. However, challenges remain, including difficulty replicating human atherosclerosis in preclinical models, regulatory concerns about long-term safety, and ensuring accessibility in low-resource settings. In addition, large and diverse clinical trials are needed to confirm the efficacy of these vaccines in reducing cardiovascular events.

Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). BI 1361849 (formerly CV9202) is a cancer vaccine comprising 6 mRNA constituents, each of which encodes for one of the non-small cell lung cancer (NSCLC) associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2, and MAGE-C1. Durvalumab (durva) is a checkpoint inhibitor that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 (PD-1). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. Tremelimumab (treme) is an anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) blocking antibody. Targeting both the CTLA-4 and PD-1 checkpoint pathways provides the potential for additive or synergistic effects. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine, BI 1361849, can enhance the activity of checkpoint blockade. This ongoing phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in patients with NSCLC. In Arm A, an initial dose evaluation phase follows a 3+3 design to confirm the dose of durva (full dose 1500 mg or de-escalated 750 mg, if needed) to be given with the vaccine. Arm B uses the dose established in Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n=10), in which patients receive the checkpoint inhibitor(s) only. Study treatment is administered over 12 cycles (28 days each). Durva (x 12 doses) and treme (x 4 doses, Arm B only) are administered intravenously every 28 days. The vaccine is administered as a total of 14 doses (of the 6 components) during the 12 cycles, using a device that provides a needle-free intradermal administration. The primary endpoint is assessment of safety and tolerability, including evaluation of dose-limiting toxicities. Secondary endpoints include progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST 1.1 and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20 December 2017. As of 27 June 2018, 2 patients are enrolled; enrollment is ongoing. Citation Format: Joshua Sabari, Kristen Aufiero Ramirez, Paul Schwarzenberger, Toni Ricciardi, Mary Macri, Aileen Ryan, Ralph Venhaus. Phase 1/2 study of mRNA vaccine therapy + durvalumab (durva) ± tremelimumab (treme) in patients with metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B209.

The prognosis for patients with glioblastoma multiforme (GBM), an aggressive and deadly brain tumor, is poor due to the limited therapeutic options available. Biomimetic nanoparticles have emerged as a promising vehicle for targeted mRNA vaccine delivery, thanks to recent advances in nanotechnology. This presents a novel treatment method for GBM. This review explores the potential of using biomimetic nanoparticles to improve the specificity and effectiveness of mRNA vaccine against GBM. These nanoparticles can evade immune detection, cross the blood–brain barrier, & deliver mRNA directly to glioma cells by mimicking natural biological structures. This allows glioma cells to produce tumor-specific antigens that trigger strong immune responses against the tumor. This review discusses biomimetic nanoparticle design strategies, which are critical for optimizing transport and ensuring targeted action. These tactics include surface functionalization and encapsulation techniques. It also highlights the ongoing preclinical research and clinical trials that demonstrate the therapeutic advantages and challenges of this strategy. Biomimetic nanoparticles for mRNA vaccine delivery represent a new frontier in GBM treatment, which could impact the management of this deadly disease and improve patient outcomes by integrating cutting-edge nanotechnology with immunotherapy.

Cationic polymers have garnered considerable attention as mRNA carriers due to their structural tunability and chemical diversity. Nevertheless, their broader application remains limited by poor stability under physiological conditions and cytotoxicity associated with excessive charge density. Here, we report thiourea-modified poly(l-lysine) (PLL-T) carriers constructed by combinatorial side-chain modification with ionizable and hydrophobic isothiocyanates. The resulting thiourea linkage introduced two hydrogen bonding donor sites, enabling stronger hydrogen bonding with mRNA. These hydrogen bonding could synergize with electrostatic and hydrophobic interactions, forming multiple cooperative interactions with mRNA. This design enhanced mRNA encapsulation, colloidal stability, and high transfection efficiency without increasing cytotoxicity. The optimized PLL-1A1B(T) variant achieved over 10,000-fold higher transfection efficiency than the parent polymer PLL, and outperformed the commercial gold-standard Lipofectamine MessengerMAX in both HEK293T and RAW264.7 cells. Compared with its amide-linked analogue PLL-1A1B(A), in which the amide linkage provided only a single hydrogen bonding donor site, PLL-1A1B(T) exhibited superior mRNA encapsulation (91 % vs. 42 %), higher storage stability, and over 50-fold increase in intramuscular transfection. Unlike PLL-1A1B(A), which induced high levels of inflammation, PLL-1A1B(T) exhibited minimal inflammation in vivo. Importantly, PLL-1A1B(T) enabled efficient delivery of mRNA cancer vaccines and elicited potent CD8+ T cell mediated antitumor immunity. A single administration of PLL-1A1B(T)@E6/E7 mRNA vaccine achieved 77 % tumor suppression rate (TSR) in the TC-1 tumor model. Moreover, in combination with anti PD-1, PLL-1A1B(T)@OVA mRNA vaccine achieved 90 % TSR in the B16-OVA tumor model. This study demonstrates hydrogen bonding-driven carriers engineering as a versatile strategy to tune nucleic acid-carrier interactions, offering a potent and safe platform for mRNA therapeutics.

mRNA-based gene therapy drugs and preventive vaccines have become a hot topic of development. The technical principle is that mRNA delivered to the body cells can be expressed through the translation mechanism of host cells to produce therapeutic proteins or immunogenic proteins, which have therapeutic effects on the body or stimulate the body to produce immune effects. mRNA vaccines have many advantages over traditional vaccines, such as their safety, flexibility, rapid production and low cost. mRNA vaccines are therefore proposed as a new frontier in vaccination. in this review, the main key technologies based on mRNA drug design, such as in vitro transcription (IVT), nucleotide and cap and tail structure modification, were reviewed, followed by a brief introduction to mRNA purification methods and delivery systems. Several novel mRNA drugs are also briefly described. Finally, the latest research directions and possible challenges of mRNA are mentioned, aiming to provide support for the development of mRNA gene therapy drugs and vaccines.