Active Targeting Ligand Research Articles

Chemo-Enzymatic Functionalization of Bovine Milk Exosomes with an EGFR Nanobody for Target-specific Drug Delivery.

Bovine milk exosomes (BmExo) have been identified as versatile nanovesicles for anti-cancer drugs delivery due to their natural availability and biocompatibility. However, tumor-specific delivery based on BmExo often requires post-isolation modifications of the membrane surface with active-targeting ligands. In this study, we report an alternative approach to functionalize BmExo with nanobody combining facile chemical modification and Sortase A-mediated site-specific ligation, as demonstrated by the development of an epidermal growth factor receptor (EGFR)-targeted drug delivery system. The BmExo membrane was first coated with a diglycine-containing amphiphile molecule, NH2-GG-PEG2000-DSPE, by hydrophobic insertion. The diglycine as nucleophiles displayed on the membrane enabled the subsequent ligation of the EGFR nanobody (7D12) by Sortase A (SrtA)-mediated site-specific transpeptidation. The successful construction of BmExo-7D12 was confirmed by Western blotting analysis, electron microscopy, and dynamic light scattering (DLS). As a demonstration model, BmExo-7D12 loaded with the chemotherapeutic drug doxorubicin (Dox) was shown to be able to deliver Dox to cancer cells in response to the expression of EGFR as manifested by immunocytochemistry and flow cytometry analysis. Finally, the cytotoxicity assay showed that BmExo-7D12-Dox was more effective in killing tumor cells with high EGFR expression while significantly reduced the non-specific toxicity to EGFR negative cells. In conclusion, these results demonstrate that 7D12-functionalized BmExo can serve as a target-specific delivery system for Dox to selectively kill EGFR-expressing tumor cells. This approach should prove to be versatile and efficient for the generation of protein-ligands modified BmExo.

Advances in active targeting of ligand-directed polymeric nanomicelles via exploiting overexpressed cellular receptors for precise nanomedicine.

Many of the utilized drugs which already exist in the pharmaceutical sector are hydrophobic in nature. These drugs are characterized by being poorly absorbed and difficult to formulate in aqueous environments with low bioavailability, which could result in consuming high and frequent doses in order to fulfil the required therapeutic effect. As a result, there is a decisive demand to find modern alternatives to overcome all these drawbacks. Self-assembling polymeric nanomicelles (PMs) with their unique structure appear to be a fascinating choice as a pharmaceutical carrier system for improving the solubility & bioavailability of many drugs. PMs as drug carriers have many advantages including suitable size, high stability, prolonged circulation time, elevated cargo capacity and controlled therapeutic release. Otherwise, the pathological features of some diseased cells, like cancer, allow PMs with particle size <200 nm to be passively uptaken via enhanced permeability and retention phenomenon (EPR). However, the passive targeting approach was proven to be insufficient in many cases. Consequently, the therapeutic efficiency of these PMs can be further reinforced by enhancing their cellular internalization via incorporating targeting ligands. These targeting ligands can enhance the assemblage of loaded cargos in the intended tissues via receptor-mediated endocytosis through exploiting receptors robustly expressed on the exterior of the intended tissue while minimizing their toxic effects. In this review, the up-to-date approaches of harnessing active targeting ligands to exploit certain overexpressed receptors will be summarized concerning the functionalization of the exterior of PMs for ameliorating their targeting potential in the scope of nanomedicine.

Actively Targeted Nanomedicines: A New Perspective for the Treatment of Pregnancy-Related Diseases.

More than 20% of pregnant women experience serious complications during pregnancy, that gravely affect the safety of both the mother and the child. Due to the unique state of pregnancy, medication during pregnancy is subject to various restrictions. Nanotechnology is an emerging technology that has been the focus of extensive medical research, and great progress has recently been made in developing sensitive diagnostic modalities and efficient medical treatment. Accumulating evidence has shown that nanodrug delivery systems can significantly improve the targeting, reduce the toxicity and improve the bioavailability of drugs. Recently, some actively targeted nanomedicines have been explored in the treatment of pregnancy-related diseases. This article reviews common types of nanocarriers and active targeting ligands in common pregnancy-related diseases and complications such as preeclampsia, preterm birth, fetal growth restriction, and choriocarcinoma. Finally, the challenges and future prospects in the development of these nanomaterials are discussed, with the aim of providing guidance for future research directions.

Active-transporting of charge-reversal Cu(II)-doped mesoporous silica nanoagents for antitumor chemo/chemodynamic therapy

Fe-based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the low pH environment and insufficient endogenous hydrogen peroxide (H2O2) of the highly efficient Fenton reaction limits its practical application in clinic. Here, a Cu(II)-doped mesoporous silica nanoagent (Cu-MSN) with excellent dispersity was successfully developed. After loaded with doxorubicin (DOX) and ascorbate (AA), Cu-MSN@DA was coated with active targeting ligand folic acid (FA), dimethyl maleic an-hydride (DMMA) and carboxymethyl chitosan (CMC) to obtain an active transporting nanoagent (FCDC@Cu-MSN@DA) with tunable charge-reversal property, which is more adaptable to the pH value of TME than Fe-based Fenton agents, and can self-supply exogenous H2O2 by ascorbate to produce more toxic ·OH to trigger the apoptosis of cancer cells. Meanwhile, the high level of glutathione (GSH) in TME can reduce Cu(II) to Cu(I) by Fenton-like reaction, increasing the generation rate of ·OH and relieving tumor antioxidant ability. The supply of exogenous H2O2 significantly enhanced the synergistic effect of CDT by oxidative damage. Together with DOX-induced cell apoptosis, this novel nanoagent FCDC@Cu-MSN@DA can achieve maximum therapeutic efficacy, creating a new model of safe and effective tumor treatment with high specificity.

Hyaluronic Acid-Bilirubin Nanoparticles as a Tumor Microenvironment Reactive Oxygen Species-Responsive Nanomedicine for Targeted Cancer Therapy.

The tumor microenvironment (TME) has attracted considerable attention as a potential therapeutic target for cancer. High levels of reactive oxygen species (ROS) in the TME may act as a stimulus for drug release. In this study, we have developed ROS-responsive hyaluronic acid-bilirubin nanoparticles (HABN) loaded with doxorubicin (DOX@HABN) for the specific delivery and release of DOX in tumor tissue. The hyaluronic acid shell of the nanoparticles acts as an active targeting ligand that can specifically bind to CD44-overexpressing tumors. The bilirubin core has intrinsic anti-cancer activity and ROS-responsive solubility change properties. DOX@HABN showed the HA shell-mediated targeting ability, ROS-responsive disruption leading to ROS-mediated drug release, and synergistic anti-cancer activity against ROS-overproducing CD44-overexpressing HeLa cells. Additionally, intravenously administered HABN-Cy5.5 showed remarkable tumor-targeting ability in HeLa tumor-bearing mice with limited distribution in major organs. Finally, intravenous injection of DOX@HABN into HeLa tumor-bearing mice showed synergistic anti-tumor efficacy without noticeable side effects. These findings suggest that DOX@HABN has significant potential as a cancer-targeting and TME ROS-responsive nanomedicine for targeted cancer treatment.

Long-circulating nanoparticles as passive targeting nanocarriers for the treatment of thrombosis.

Thrombosis is the major cause of cardiovascular diseases. Only a small subset of patients could benefit from thrombolytic therapy due to the high bleeding risk brought about by the repeated administration of thrombolytic drugs. Nanoparticles with targeting ligands have been developed as nanocarriers of thrombolytic drugs to deliver the drug to the thrombus through active targeting. However, the passive targeting effect of nanoparticles on the thrombus is yet to be investigated. Herein, we prepared silica cross-linked micelles (SCLMs) with a long blood circulation half-life as drug carriers to target the thrombus through passive targeting. Compared with SCLMs modified with an active targeting ligand cRGD, the SCLMs exhibited similar targeting behavior to the thrombus in vivo. Loaded with the thrombolytic drug tirofiban, the passive targeting SCLMs showed a comparable therapeutic effect to cRGD-modified SCLMs in a mice model with pulmonary embolism and arterial thrombosis.

Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.

Chimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B-cell lymphoma (BL). However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment. Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used. Optimized Spleen SORT LNPs containing 10 % 18 : 1 PA transfected CD3+, CD8+, and CD4+ T cells in wild-type mice. Spleen SORT LNPs delivered Cre recombinase mRNA and CAR encoding mRNA to T cells in reporter mice and in a lymphoreplete B cell lymphoma model (respectively) after intravenous injection without the need for active targeting ligands. Moreover, in situ CAR T cells increased the overall survival of mice with a less aggressive form of B cell lymphoma. In addition, in situ transfected CAR T cells reduced tumor metastasis to the liver by increasing tumor infiltrating lymphocytes. Overall, these results offer a promising alternative method for CAR T cell production with pre-clinical potential to treat hematological malignancies.

Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma

AbstractChimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B‐cell lymphoma (BL). However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment. Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used. Optimized Spleen SORT LNPs containing 10 % 18 : 1 PA transfected CD3+, CD8+, and CD4+ T cells in wild‐type mice. Spleen SORT LNPs delivered Cre recombinase mRNA and CAR encoding mRNA to T cells in reporter mice and in a lymphoreplete B cell lymphoma model (respectively) after intravenous injection without the need for active targeting ligands. Moreover, in situ CAR T cells increased the overall survival of mice with a less aggressive form of B cell lymphoma. In addition, in situ transfected CAR T cells reduced tumor metastasis to the liver by increasing tumor infiltrating lymphocytes. Overall, these results offer a promising alternative method for CAR T cell production with pre‐clinical potential to treat hematological malignancies.

RGD-engineered nanoparticles as an innovative drug delivery system in cancer therapy

The poor efficiency and drastic adverse effects of current cancer therapies entail a radical shift in treatment paradigms, which require developing cutting-edge therapeutics in laboratories and bringing them to rigorous preclinical and clinical testing. The principal drawbacks of present cancer therapies are the incapability of tumor targeting, uneven drug accumulation at the site of action, and poor tumor monitoring. Accordingly, incorporating nanoparticles (NPs) has made clinical progress in conveying conventional or candidate therapeutic molecules to the site of action, encouraging anticancer impacts. Interestingly, modern cancer therapy has lately been redefined by the functionalizing NPs with active targeting ligands like the Arginine-Glycine-Aspartic acid (RGD) peptide, remarkably strengthening the therapeutic outcomes and diminishing off-target effects. The overexpression of integrin receptors on the surface of cancerous cells brought a unique opportunity for cancer-targeted drug delivery since RGD-decorated nanocarriers precisely recognize these receptors and selectively transport their chemotherapeutic or diagnostic payloads to the cancerous cells. Subsequently, RGD-conjugated NPs have frequently been enlisted for cancer diagnosis and imaging-guided surgery, improving therapeutics strength and overwhelming drug resistance. Here, we discussed the relevance of integrin receptors in carcinogenesis and thoroughly deliberated the potential of RGD-functionalized NPs as innovative drug delivery platforms in modern cancer therapy.

Thermal immuno-nanomedicine: A new strategy for cancer treatment.

Thermal immuno-nanomedicine: A new strategy for cancer treatment.

Research Advances in Nucleic Acid Delivery System for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the lives of nearly 1% of the total population worldwide. With the understanding of RA, more and more therapeutic drugs have been developed. However, lots of them possess severe side effects, and gene therapy may be a potential method for RA treatment. A nanoparticle delivery system is vital for gene therapy, as it can keep the nucleic acids stable and enhance the efficiency of transfection in vivo. With the development of materials science, pharmaceutics and pathology, more novel nanomaterials and intelligent strategies are applied to better and safer gene therapy for RA. In this review, we first summarized the existing nanomaterials and active targeting ligands used for RA gene therapy. Then, we introduced various gene delivery systems for RA treatment, which may enlighten the relevant research in the future.

Preparation and Evaluation of 64Cu-Radiolabled Dual-Ligand Multifunctional Gold Nanoparticles for Tumor Theragnosis.

Gold nanoparticles (AuNPs) are cutting-edge platforms for combined diagnostic and therapeutic approaches due to their exquisite physicochemical and optical properties. Using the AuNPs physically produced by femtosecond pulsed laser ablation of bulk Au in deionized water, with a capping agent-free surface, the conjugation of functional ligands onto the AuNPs can be tunable between 0% and 100% coverage. By taking advantage of this property, AuNPs functionalized by two different types of active targeting ligands with predetermined ratios were fabricated. The quantitatively controllable conjugation to construct a mixed monolayer of multiple biological molecules at a certain ratio onto the surface of AuNPs was achieved and a chelator-free 64Cu-labeling method was developed. We report here the manufacture, radiosynthesis and bioevaluation of three different types of dual-ligand AuNPs functionalized with two distinct ligands selected from glucose, arginine-glycine-aspartate (RGD) peptide, and methotrexate (MTX) for tumor theragnosis. The preclinical evaluation demonstrated that tumor uptakes and retention of two components AuNP conjugates were higher than that of single-component AuNP conjugates. Notably, the glucose/MT- modified dual-ligand AuNP conjugates showed significant improvement in tumor uptake and retention. The novel nanoconjugates prepared in this study make it possible to integrate several modalities with a single AuNP for multimodality imaging and therapy, combining the power of chemo-, thermal- and radiation therapies together.

Exploiting Nanoparticles for Blood-Brain Barrier Permeation: A Promising Paradigm in Neurotherapeutics

Nano particles are widely used in the drug delivery systems to improve efficacy, bioavailability and targeted delivery of therapeutic agents. They are typically ranging from the 1-100 nm in size and emerged as versatile tools in the field of drug delivery, revolutionizing the way therapeutic agents are transported and released within the human body. Role played by nanoparticles in crossing physiological barriers and enhancing the efficacy of therapeutic decisions. Nanoparticles exhibit unique physicochemical properties that enable them to navigate the intricate biological milieu and optimize drug delivery. The Blood Brain Barrier (BBB’s) intricate structure and its pivotal role in maintaining neural homeostasis Endothelial cells, tight junctions, and efflux transporters make up the majority of this specific barrier, which has historically made it difficult to deliver medications and therapeutic agents to the brain. These problems can only be solved by using nanoparticles’ unique physical and biological characteristics, which also provide a wide variety of nanocarriers and methods for improving BBB permeability. Nanoparticles use a variety of techniques to improve their interactions with the BBB, such as size optimization, surface charge alteration, and active targeting ligands the interplay of these mechanisms serves to overcome the physical and biochemical restrictions, allowing for controlled and targeted drug delivery to specific brain regions.

Folic acid-poly(N-isopropylacrylamide-maltodextrin) nanohydrogels as novel thermo-/pH-responsive polymer for resveratrol breast cancer targeted therapy

BackgroundThe long-term sequelae and serious side effects of conventional breast cancer chemotherapy due to ubiquitous biodistribution and systemic toxicity remain the main obstacle to success in clinic. Recent anticancer research rely on tailoring smart carriers to overcome these drawbacks. In this regard, numerous stimuli-responsive polymers have been assembled and successfully employed as smart carriers various chemotherpeutic agents due to their intrinsic tumor targeting properties. Among which, poly(N-isopropylacrylamide (PNIPAM) has gained increasing attention being amenable to various chemical modifications for tuning its intrinsic thermoresponsivity or endowing additional stimulus responsiveness. This work aims to develop PNIPAM-maltodextrin nanohydrogels (PNIPAM-MD NGs) decorated with folic acid (FA) as smart breast cancer-targeted stimuli-responsive delivery system to the natural polyphenol resveratrol (RSV) suffering from low bioavailaibity. ResultsPNIPAM-MD was synthesized by graft copolymerization, characterized and evaluated for its modulated stimuli-responsivity. The PNIPAM-based copolymer was coupled with FA, the breast cancer active targeting ligand. The FA-PNIPAM-MD NGs core was loaded RSV, then subjected to in vitro and in vivo evaluation. Results showed that the developed RSV-loaded FA-PNIPAM-MD (F3) NGs displayed dual thermo- and pH-responsivities, high drug-loading capacity (8.31 wt%,) and excellent physical and serum stability. The targeted formula F3 exhibited enhanced in vitro anti-breast cancer potency as evident by 7.4 folds reduction in the IC50 of free RSV and significant MCF-7 cellular uptake. In breast cancer-bearing mice, F3 suppressed the tumor growth, lowered VEGF-1 and Ki-67 expression levels, and induced apoptosis via upregulating caspase-3. ConclusionOverall, the PNIPAM-MD NGs as well as its FA-decorated breast cancer-targted NGs could serve as promising smart nanocarrier for efficient RSV brest cancer delivery. It could be safely deduced that the assembled FA-PNIPAM-MD F3 NGs enabled sequestering the therapeutic cargo (RSV) in normal tissue and released it in tumor site, thus guarding against its rapid metabolism and maximizing its accumulation in the cancer tissue as evidenced by the remarkable tumor growth suppression noticed in the targeted RSV/FA-PNIPAM-MD F3 NGs-treated mice compared to that in the free RSV-treated group. Hence, The fabricated nanohydrogels may be further employed for smart delivery of various anti-breast cancer agents.

Delivery of Theranostic Nanoparticles to Various Cancers by Means of Integrin-Binding Peptides.

Active targeting of tumors is believed to be the key to efficient cancer therapy and accurate, early-stage diagnostics. Active targeting implies minimized off-targeting and associated cytotoxicity towards healthy tissue. One way to acquire active targeting is to employ conjugates of therapeutic agents with ligands known to bind receptors overexpressed onto cancer cells. The integrin receptor family has been studied as a target for cancer treatment for almost fifty years. However, systematic knowledge on their effects on cancer cells, is yet lacking, especially when utilized as an active targeting ligand for particulate formulations. Decoration with various integrin-targeting peptides has been reported to increase nanoparticle accumulation in tumors ≥ 3-fold when compared to passively targeted delivery. In recent years, many newly discovered or rationally designed integrin-binding peptides with excellent specificity towards a single integrin receptor have emerged. Here, we show a comprehensive analysis of previously unreviewed integrin-binding peptides, provide diverse modification routes for nanoparticle conjugation, and showcase the most notable examples of their use for tumor and metastases visualization and eradication to date, as well as possibilities for combined cancer therapies for a synergetic effect. This review aims to highlight the latest advancements in integrin-binding peptide development and is directed to aid transition to the development of novel nanoparticle-based theranostic agents for cancer therapy.

Efficacy analysis of targeted nanodrug for non-small cell lung cancer therapy.

Biological macromolecules have been widely used as biomedical carriers in treating non-small cell lung cancer (NSCLC) due to their biocompatibility, targeting, biodegradability, and antitumor efficacy. Nanotechnology has been used in clinics to treat many diseases, including cancer. Nanoparticles (NPs) can accumulate drugs into tumors because of their enhanced permeability and retention (EPR) effects. However, the lack of active targeting ligands affects NPs drug delivery. Arginine-glycine-aspartic (RGD), as a targeting ligand, has distinct advantages in targeting and safety. In the present study, an RGD peptide-modified nanogel called RGD-polyethylene glycol-poly (L-phenylalanine-co-L-cystine) (RGD-PEG-P (LP-co-LC-P (LP-co-LC) was investigated to deliver vincristine (VCR) as NSCLC therapy. The VCR-loaded targeted nanoparticle (RGD-NP/VCR) demonstrated excellent antitumor efficacy compared to the free drug (VCR) and untargeted nanoparticle (NP/VCR) without any significant side effects. RGD-NP/VCR has better tumor inhibition and fewer side effects, indicating its potential benefit in NSCLC treatment.

A multifunctional non-viral vector for the delivery of MTH1-targeted CRISPR/Cas9 system for non-small cell lung cancer therapy

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system adapted from bacteria is a programmable nuclease-based genome editing tool. The long-lasting effect of gene silencing or correction is beneficial in cancer treatment. Considering the need to broaden the practical application of this technology, highly efficient non-viral vectors are urgently required. We prepared a multifunctional non-viral vector that could actively target tumor cells and deliver CRISPR/Cas9 plasmids into nuclei of cancer cells. Protamine sulfate (PS) which contains nuclear localization sequence was utilized to condense plasmid DNA and facilitate nuclei-targeted delivery. Liposome-coated protein/DNA complex avoided the degradation of nuclease in blood circulation. The obtained PS@Lip/pCas9 was further modified with distearoyl phosphoethanolamine-polyethylene glycol-hyaluronic acid (HA) to endow the vector ability to actively target tumor cell. Results suggested that PS@HA-Lip could deliver CRISPR/Cas9 plasmids into nuclei of tumor cells and induce genome editing effect. With the disruption of MTH1 (mutT homolog1) gene, the growth of non-small cell lung cancer was inhibited. Moreover, cell apoptosis in tumor tissue was promoted, and liver metastasis of non-small cell lung cancer (NSCLC) was reduced. Our study has provided a therapeutic strategy targeting MTH1 gene for NSCLC therapy. Statement of significanceCRISPR/Cas9 as a powerful tool for genome editing has drawn much attention. The long-lasting effect possesses unique advantage in cancer treatment. Non-viral vectors have high loading capacity, high safety and low immunogenicity, playing an important role in CRISPR/Cas9 delivery. In our study, a multifunctional non-viral vector for the efficient delivery of CRISPR/Cas9 plasmid was constructed. With the active targeting ligand and nuclei-targeting component, the cargo was efficiently delivered into cell nuclei and exerted genome editing effect. By using this vector, we successfully inhibited the growth and induced the apoptosis of non-small cell lung cancer by disrupting MTH1 expression with good safety. Our work provided an efficient non-vial vector for CRISPR/Cas9 delivery and explored the possibility for cancer treatment.

Pitavastatin-loaded bilosomes for oral treatment of hepatocellular carcinoma: a repurposing approach

Albeit its established efficacy as an anti-hyperlipidemic agent, pitavastatin (PIT) has been shown to have other various therapeutic effects. One of these effects is the anti-cancer activity against hepatocellular carcinoma (HCC). This effect has been evaluated in this study for the first time via its oral delivery loaded in bilosomes both in vitro in hepatocellular carcinoma (HCC) cell line; HepG2 and in vivo in an Ehrlich ascites carcinoma (EAC) model. Moreover, the impact of surface modification of bilosomes with lactoferrin (LF) as an active targeting ligand for HCC was investigated. Bilosomes were prepared by thin-film hydration and different molar phospholipid to bile salt ratios were used to optimize the bilosomal formulation. The molar phospholipid to bile salt ratio was adjusted to 4:1 at pH 7.4. LF-coated bilosomes possessed a particle size, PDI, entrapment efficiency, and zeta potential of 112.28 nm ± 6.35, 0.229 ± 0.06, 90.56% ± 3.22, and −7.86 mV ± 1.13, respectively. LF-coated bilosomes also increased permeation of PIT when tested on Caco-2 cells by 3.1-folds (compared to uncoated ones or free PIT solution). It also improved the cytotoxicity of HepG2 spheroids 44-folds more than PIT-free solution. RT-PCR analysis showed that LF-coated PIT-loaded bilosomes caused an improvement (2-fold increase) in the apoptotic potential of PIT mediated by caspase-3. In conclusion, the optimized LF-coated PIT-loaded bilosomes were cytotoxic to HCC with improved hepatocytes permeation and cellular uptake. Thus, the proposed formula could be a promising treatment for HCC.

Organic Small Molecule Contrast Agent for Targeted Photoacoustic Imaging of Patient-Derived Brain Tumors.

Traditional glioblastoma (GBM) cell lines do not maintain the heterogeneity of the original tumor, cell interactions, and therapy response, thus limiting their investigation in GBM theranostics. Herein, a kind of GBM tumor-targeting nanoparticles (NPs) TCFNP@iRGD are designed and constructed, which are generated by photoacoustic (PA) contrast agent 2-(3-cyano-4,5,5-trimethylfuran-2(5H)-ylidene) malononitrile (TCF)-OH through facile nanoprecipitation and decorated with an active targeting ligand iRGD. Their potential in GBM detection via PA imaging on glioma patient-derived cells intracranial xenograft models is evaluated for the first time. Excellent tumor-specific PA mapping performance of GBM is realized by TCFNP@iRGD, demonstrating its promising potential in the clinical diagnosis of GBM.

Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for invivo 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.