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The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8⁺ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen–bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180–188)–encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti–programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

Therapeutic tumor vaccines have attracted considerable attention in the past decade; they can induce tumor regression, eradicate minimal residual disease, establish lasting immune memory and avoid non-specific and adverse side effects. However, the challenge in the field of therapeutic tumor vaccines is ensuring the delivery of immune components to the lymph nodes (LNs) to activate immune cells. The clinical response rate of traditional therapeutic tumor vaccines falls short of expectations due to inadequate lymph node delivery. With the rapid development of nanotechnology, a large number of nanoplatform-based LN-targeting nanovaccines have been exploited for optimizing tumor immunotherapies. In addition, some nanovaccines possess non-invasive visualization performance, which is benefit for understanding the kinetics of nanovaccine exposure in LNs. Herein, we present the parameters of nanoplatforms, such as size, surface modification, shape, and deformability, which affect the LN-targeting functions of nanovaccines. The recent advances in nanoplatforms with different components promoting LN-targeting are also summarized. Furthermore, emerging LNs-targeting nanoplatform-mediated imaging strategies to both improve targeting performance and enhance the quality of LN imaging are discussed. Finally, we summarize the prospects and challenges of nanoplatform-based LN-targeting and /or imaging strategies, which optimize the clinical efficacy of nanovaccines in tumor immunotherapies.

Targeted delivery of nucleic acids to lymph nodes is critical for the development of effective vaccines and immunotherapies. However, it remains challenging to achieve selective lymph node delivery. Current gene delivery systems target mainly to the liver and typically exhibit off-target transfection at various tissues. Here we report novel lipid nanoparticles (LNPs) that can deliver plasmid DNA (pDNA) to a draining lymph node, thereby significantly enhancing transfection at this target organ, and substantially reducing gene expression at the intramuscular injection site (muscle). In particular, we discovered that LNPs stabilized by 3% Tween 20, a surfactant with a branched poly(ethylene glycol) (PEG) chain linking to a short lipid tail, achieved highly specific transfection at the lymph node. This was in contrast to conventional LNPs stabilized with a linear PEG chain and two saturated lipid tails (PEG-DSPE) that predominately transfected at the injection site (muscle). Interestingly, replacing Tween 20 with Tween 80, which has a longer unsaturated lipid tail, led to a much lower transfection efficiency. Our work demonstrates the importance of PEGylation in selective organ targeting of nanoparticles, provides new insights into the structure–property relationship of LNPs, and offers a novel, simple, and practical PEGylation technology to prepare the next generation of safe and effective vaccines against viruses or tumours.

Several recent attempts to improve the stability and immunogenicity of messenger RNA (mRNA) vaccines include the use of circular RNA (circRNA), targeted delivery, and lyophilization. However, these research directions have often been pursued independently, ignoring the impact of the modification of lipid nanoparticle-encapsulated mRNA vaccines on their targeted delivery after lyophilization and on their subsequent immunogenicity. Here, we develop a circRNA vaccine targeting lymph nodes that expresses rabies virus glycoprotein (G), termed circRNA-G. Mannose modification is introduced directly into the process of synthesizing PEG lipids, and the resulting PEG-mannose can be used in the preparation of mannose-LNPs (mLNPs) that target dendritic cells, thereby promoting the specific distribution of circRNA-G to lymph nodes (mLNP-circRNA-G). We demonstrated that mLNP-circRNA-G has continuous antigen availability that promotes the generation of T follicular helper cells, germinal center B cells, long-lived plasma cells, and memory B cells in mice. Importantly, the vaccine with this targeting modification remained stable for at least 24 weeks of storage at 4℃ after lyophilization, and its immunogenicity was also maintained. Notably, this strategy also enhances the antibody production of the SARS-CoV-2 trimeric receptor-binding domain circRNA vaccine and the stability of immunogenicity after lyophilization. In summary, this study provides a general platform for the design of lyophilized vaccines with targeted stability, demonstrating the potential of lymph node-targeting circRNAs as next-generation vaccines. messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the nonspecificity of lipid nanoparticle-encapsulated (LNP) delivery systems result in the need for cold storage and a relatively short-duration immune response to mRNA vaccines. Herein, we develop a novel vaccine in the form of circRNAs encapsulated in LNPs, and the circular structure of the circRNAs enhances their stability. Lyophilization is considered the most effective method for the long-term preservation of RNA vaccines. However, this process may result in irreversible damage to the nanoparticles, particularly the potential disruption of targeting modifications on LNPs. During the selection of lymph node-targeting ligands, we found that LNPs modified with mannose maintained their physical properties almost unchanged after lyophilization. Additionally, the targeting specificity and immunogenicity remained unaffected. In contrast, even with the addition of cryoprotectants such as sucrose, the physical properties of LNPs were impaired, leading to an obvious decrease in immunogenicity. This may be attributed to the protective role of mannose on the surface of LNPs during lyophilization. Freshly prepared and lyophilized mLNP-circRNA vaccines elicited comparable immune responses in both the rabies virus model and the SARS-CoV-2 model. Our data demonstrated that mLNP-circRNA vaccines elicit robust immune responses while improving stability after lyophilization, with no compromise in tissue targeting specificity. Therefore, mannose-modified LNP-circRNA vaccines represent a promising vaccine design strategy.

Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine production, inefficient delivery to STING, and rapid clearance. In addition, a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist molecules are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDG SF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo experiments, we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.

Subunit vaccines are an important platform for controlling current and emerging infectious diseases. The lymph nodes are the primary site generating the humoral response and delivery of antigens to these sites is critical to effective immunization. Indeed, the duration of antigen exposure within the lymph node is correlated with the antibody response. While current licensed vaccines are typically given through the intramuscular route, injecting vaccines subcutaneously allows for direct access to lymphatic vessels and therefore can enhance the transfer of antigen to the lymph nodes. However, protein subunit antigen uptake into the lymph nodes is inefficient, and subunit vaccines require adjuvants to stimulate the initial immune response. Therefore, formulation strategies have been developed to enhance the exposure of subunit proteins and adjuvants to the lymph nodes by increasing lymphatic uptake or prolonging the retention at the injection site. Given that lymph node exposure is a crucial consideration in vaccine design, in depth analyses of the pharmacokinetics of antigens and adjuvants should be the focus of future preclinical and clinical studies. This review will provide an overview of formulation strategies for targeting the lymphatics and prolonging antigen exposure and will discuss pharmacokinetic evaluations which can be applied toward vaccine development.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with pathogenic inflammation caused partly by excessive cell‐free DNA (cfDNA). Specifically, cfDNA is internalized into immune cells, such as macrophages in lymphoid tissues and joints, and activates pattern recognition receptors, including cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS), resulting in overly strong proinflammation. Here, nanomedicine‐in‐hydrogel (NiH) is reported that co‐delivers cGAS inhibitor RU.521 (RU) and cfDNA‐scavenging cationic nanoparticles (cNPs) to draining lymph nodes (LNs) for systemic immunosuppression in RA therapy. Upon subcutaneous injection, NiH prolongs LN retention of RU and cNPs, which pharmacologically inhibit cGAS and scavenged cfDNA, respectively, to inhibit proinflammation. NiH elicits systemic immunosuppression, repolarizes macrophages, increases fractions of immunosuppressive cells, and decreases fractions of CD4 + T cells and T helper 17 cells. Such skewed immune milieu allows NiH to significantly inhibit RA progression in collagen‐induced arthritis mice. These studies underscore the great potential of NiH for RA immunotherapy.

The clinical efficacy of personalized cancer vaccines still needs to be improved due to their insufficient immune effect. The development of innovative adjuvants and lymph node‐targeted delivery systems is the key to improving the clinical efficacy of personalized vaccines. However, there is still a lack of an adjuvant delivery system that is simple in preparation and capable of mass production and integrates adjuvant and lymph node targeted delivery functions. Here, this work reports that a simple dendrimer polypeptide (KK2DP7) nanoparticle enhances the immune efficacy of an OVA/neoantigen‐based vaccine. Due to its multiple functions as a delivery vehicle, immune adjuvant, and facilitator of dendritic cell migration, KK2DP7 efficiently increases the efficiency of antigen uptake and cross‐presentation by antigen‐presenting cells (APCs) and delivers antigens to lymph nodes via APCs. Strikingly, the antitumor effect of KK2DP7/OVA is superior to that of commonly used adjuvants such as poly(I:C), CpG, and aluminum adjuvant combined with OVA. Furthermore, KK2DP7/OVA combined with anti‐PD‐1 antibody is able to prevent tumor recurrence in a postoperative recurrent tumor model. Thus, KK2DP7‐based cancer vaccines alone or in combination with immune checkpoint blockade therapies to treat tumors or postoperative tumor recurrence are a powerful strategy to enhance antitumor immunity. KK2DP7 in combination with OVA can form nanovaccine that can target lymph nodes after subcutaneous injection. As a delivery vehicle, it can efficiently deliver OVA to DCs via caveolin‐ and clathrin‐dependent pathways. As an immune adjuvant, it can stimulate DC maturation by activating the TLR2‐NF‐κB signaling pathway, increasing the efficiency of DC cross‐presentation to antigens and inducing subsequent immune responses.

Immunotherapy has been recognized as one of the most promising treatment strategies for head and neck squamous cell carcinoma (HNSCC). As a pioneering trend of immunotherapy, dendritic cell (DC) vaccines have displayed the ability to prime an immune response, while the insufficient immunogenicity and low lymph node (LN) targeting efficiency, resulted in an unsubstantiated therapeutic efficacy in clinical trials. Herein, a hybrid nanovaccine (Hy‐M‐Exo) is developed via fusing tumor‐derived exosome (TEX) and dendritic cell membrane vesicle (DCMV). The hybrid nanovaccine inherited the key protein for lymphatic homing, CCR7, from DCMV and demonstrated an enhanced efficiency of LN targeting. Meanwhile, the reserved tumor antigens and endogenous danger signals in the hybrid nanovaccine activated antigen presenting cells (APCs) elicited a robust T‐cell response. Moreover, the nanovaccine Hy‐M‐Exo displayed good therapeutic efficacy in a mouse model of HNSCC. These results indicated that Hy‐M‐Exo is of high clinical value to serve as a feasible strategy for antitumor immunotherapy. Hybridize immunogenic tumor derived exosome (TEX) with CCR7 retained dendritic cell membrane vesicle (DCMV), and adjuvanted by MPLA, to develop a novel nanovaccine (Hy‐M‐Exo), which can target in lymph nodes via the CCR7‐CCL21 way. Hy‐M‐Exo elicits robust tumor‐specific T cells infiltrated in the tumor site, alters the tumor microenvironment, and leads to tumor regression.

Background Targeting EBV-proteins with mRNA vaccines is a promising way to treat EBV-related tumors like nasopharyngeal carcinoma (NPC). We assume that it may sensitize tumors to immune checkpoint inhibitors. Results We developed an LMP2-mRNA lipid nanoparticle (C2@mLMP2) that can be delivered to tumor-draining lymph nodes. C2@mLMP2 exhibited high transfection efficiency and lysosomal escape ability and induced an increased proportion of CD8 + central memory T cells and CD8 + effective memory T cells in the spleen of the mice model. A strong synergistic anti-tumor effect of C2@mLMP2 in combination with αPD-1 was observed in tumor-bearing mice. The mechanism was identified to be associated with a reverse of CD8 + T cell exhaustion in the tumor microenvironment. The pathological analysis further proved the safety of the vaccine and the combined therapy. Conclusions This is the first study proving the synergistic effect of the EBV-mRNA vaccine and PD-1 inhibitors for EBV-related tumors. This study provides theoretical evidence for further clinical trials that may expand the application scenario and efficacy of immunotherapy in NPC. Graphical Abstract