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A targeted drug delivery system is the need of the hour. Guiding magnetic iron oxide nanoparticles with the help of an external magnetic field to its target is the principle behind the development of superparamagnetic iron oxide nanoparticles (SPIONs) as novel drug delivery vehicles. SPIONs are small synthetic γ-Fe₂O₃ (maghemite) or Fe₃O₄ (magnetite) particles with a core ranging between 10 nm and 100 nm in diameter. These magnetic particles are coated with certain biocompatible polymers, such as dextran or polyethylene glycol, which provide chemical handles for the conjugation of therapeutic agents and also improve their blood distribution profile. The current research on SPIONs is opening up wide horizons for their use as diagnostic agents in magnetic resonance imaging as well as for drug delivery vehicles. Delivery of anticancer drugs by coupling with functionalized SPIONs to their targeted site is one of the most pursued areas of research in the development of cancer treatment strategies. SPIONs have also demonstrated their efficiency as nonviral gene vectors that facilitate the introduction of plasmids into the nucleus at rates multifold those of routinely available standard technologies. SPION-induced hyperthermia has also been utilized for localized killing of cancerous cells. Despite their potential biomedical application, alteration in gene expression profiles, disturbance in iron homeostasis, oxidative stress, and altered cellular responses are some SPION-related toxicological aspects which require due consideration. This review provides a comprehensive understanding of SPIONs with regard to their method of preparation, their utility as drug delivery vehicles, and some concerns which need to be resolved before they can be moved from bench top to bedside.

mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence‐known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen‐presenting cells (APCs) can synthesize mutant neo‐antigens and multi‐antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T‐cell receptor (TCR), CD134, and immune‐modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large‐scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA‐based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA‐based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA‐based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA‐based cancer immunotherapy are also discussed. Systemic or topical mRNA delivery for immune function modulation is emerging as a promising option for cancer immunotherapy. In this review, strategies for enhancing mRNA‐based cancer immunotherapy from the perspective of mRNA structure design and delivery systems are first summarized. Advances of delivering mRNA into specific organs or cells for cancer treatment and opportunities in clinical translation are discussed.

Glioblastoma (GBM) is a central nervous system tumor with poor prognosis due to the rapid development of resistance to mono chemotherapy and poor brain targeted delivery. Chemoimmunotherapy (CIT) combines chemotherapy drugs with activators of innate immunity that hold great promise for GBM synergistic therapy. Herein, we chose temozolomide, TMZ, and the epigenetic bromodomain inhibitor, OTX015, and further co‐encapsulated them within our well‐established erythrocyte membrane camouflaged nanoparticle to yield ApoE peptide decorated biomimetic nanomedicine (ABNM@TMZ/OTX). Our nanoplatform successfully addressed the limitations in brain‐targeted drug co‐delivery, and simultaneously achieved multidimensional enhanced GBM synergistic CIT. In mice bearing orthotopic GL261 GBM, treatment with ABNM@TMZ/OTX resulted in marked tumor inhibition and greatly extended survival time with little side effects. The pronounced GBM treatment efficacy can be ascribed to three key factors: (i) improved nanoparticle‐mediated GBM targeting delivery of therapeutic agents by greatly enhanced blood circulation time and blood–brain barrier penetration; (ii) inhibited cellular DNA repair and enhanced TMZ sensitivity to tumor cells; (iii) enhanced anti‐tumor immune responses by inducing immunogenic cell death and inhibiting PD‐1/PD‐L1 conjugation leading to enhanced expression of CD4+ and CD8+ T cells. The study validated a biomimetic nanomedicine to yield a potential new treatment for GBM. We developed temozolomide and epigenetic bromodomain inhibitor co‐encapsulated biomimetic nanomedicine (ABNM@TMZ/OTX) achieved multidimensional enhanced glioblastoma synergistic chemoimmunotherapy in both primary and recurrent orthotopic mice models with significant extended survival rate and little side effects.

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue‐specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor‐targeting peptides into the LNPs; the programmed death ligand 1 (PD‐L1) binding peptides are conjugated to PEGylated lipids via a copper‐free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD‐L1 proteins, which leads to the uptake of LNPs into PD‐L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN‐deficient triple‐negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy‐mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor‐targeted LNPs for mRNA‐based cancer therapy. This study investigates a targeted delivery method for cancer therapy, using programmed death ligand 1 (PD‐L1)‐targeting lipid nanoparticles (LNPs) with PD‐L1 binding peptides attached via a copper‐free click reaction. This approach turns on phosphatase and tensin homolog (PTEN) in triple‐negative breast cancers (TNBCs), boosting autophagy, inducing immunogenic cell death (ICD)‐associated damage‐associated molecular patterns (DAMPs), promoting dendritic cell (DC) maturation, and facilitating T‐cell migration to tumors. This findings highlight the promising potential of mRNA‐based cancer therapy using these targeted LNPs.

The aim of this study was to prepare a liposomal formulation of a model drug (budesonide) for colonic delivery by incorporating a bile salt (sodium glycocholate, SGC) into liposomes followed by coating with a pH-responsive polymer (Eudragit S100, ES100). The role of the SGC is to protect the liposome from the emulsifying effect of physiological bile salts, while that of ES100 is to protect the liposomes from regions of high acidity and enzymatic activity in the stomach and small intestine. Vesicles containing SGC were prepared by two preparation methods (sonication and extrusion), and then coated by ES100 (ES100-SGC-Lip). ES100-SGC-Lip showed a high entrapment efficiency (>90%) and a narrow size distribution (particle size = 275 nm, polydispersity index < 0.130). The characteristics of liposomes were highly influenced by the concentration of incorporated SGC. The lipid/polymer weight ratio, liposome charge, liposome addition, and mixing rate were critical factors for efficient and uniform coating. In vitro drug release studies in various simulated fluids indicate a pH-dependent dissolution of the coating layer, and the disintegration process of ES100-SGC-Lip was evaluated. In conclusion, the bile salt-containing ES100-coated liposomal formulation has potential for effective oral colonic drug delivery.

The family of pH (Low) Insertion Peptides (pHLIP) comprises a tumor-agnostic technology that uses the low pH (or high acidity) at the surfaces of cells within the tumor microenvironment (TME) as a targeted biomarker. pHLIPs can be used for extracellular and intracellular delivery of a variety of imaging and therapeutic payloads. Unlike therapeutic delivery targeted to specific receptors on the surfaces of particular cells, pHLIP targets cancer, stromal and some immune cells all at once. Since the TME exhibits complex cellular crosstalk interactions, simultaneous targeting and delivery to different cell types leads to a significant synergistic effect for many agents. pHLIPs can also be positioned on the surfaces of various nanoparticles (NPs) for the targeted intracellular delivery of encapsulated payloads. The pHLIP technology is currently advancing in pre-clinical and clinical applications for tumor imaging and treatment.

Dendritic cell (DC) targeted antigen delivery is a promising strategy to enhance vaccine efficacy and delivery of therapeutics. Self-assembling peptide-based nanoparticles and virus-like particles (VLPs) have attracted extensive interest as non-replicating vectors for nanovaccine design, based on their unique properties, including molecular specificity, biodegradability and biocompatibility. DCs are specialized antigen-presenting cells involved in antigen capture, processing, and presentation to initiate adaptive immune responses. Using DC-specific ligands for targeted delivery of antigens to DCs may be utilized as a promising strategy to drive efficient and strong immune responses. In this study, several candidates for DC-binding peptides (DCbps) were individually integrated into C-terminal of porcine circovirus type 2 (PCV2) Cap, a viral protein that could self-assemble into icosahedral VLPs with 60 subunits. The immunostimulatory adjuvant activity of DC-targeted VLPs was further evaluated in a vaccine model of PCV2 Cap. With transmission electron microscopy (TEM), expressed Cap-DCbp fusion proteins were observed self-assembled into highly ordered VLPs. Further, in dynamic light scattering (DLS) analysis, chimeric VLPs exhibited similar particle size uniformity and narrow size distribution as compared to wild type Cap VLPs. With a distinctly higher targeting efficiency, DCbp3 integrated Cap VLPs (Cap-DCbp3) displayed enhanced antigen uptake and increased elicitation of antigen presentation-related factors in BM-DCs. Mice subcutaneously immunized with Cap-DCbp3 VLPs exhibited significantly higher levels of Cap-specific antibodies, neutralizing antibodies and intracellular cytokines than those with other DCbp integrated or wild type Cap VLPs without any DCbp. Interestingly, Cap-DCbp3 VLPs vaccine induces robust cellular immune response profile, including the efficient production of IFN-γ, IL-2 and IL-10. Meanwhile, the improved proliferation index in lymphocytes with Cap-DCbp3 was also detected as compared to other VLPs. This study described the potential of DC-binding peptides for further improved antigen delivery and vaccine efficacy, explainning nanovaccine optimization in relation to a range of emerging and circulating infectious pathogens.

The brain‐targeted delivery of therapeutic oligonucleotides has been investigated as a new treatment modality for various brain diseases, such as brain tumors. However, delivery efficiency into the brain has been limited due to the blood–brain barrier. In this research, brain‐targeted exosome‐mimetic cell membrane nanovesicles (CMNVs) were designed to enhance the delivery of therapeutic oligonucleotides into the brain. First, CMNVs were produced by extrusion with isolated C6 cell membrane fragments. Then, CMNVs were decorated with cholesterol‐linked T7 peptides as a targeting ligand by hydrophobic interaction, producing T7‐CMNV. T7‐CMNV was in aqueous solution maintained its nanoparticle size for over 21 days. The targeting and delivery effects of T7‐CMNVs were evaluated in an orthotopic glioblastoma animal model. 2′‐O‐metyl and cholesterol‐TEG modified anti‐microRNA‐21 oligonucleotides (AMO21c) were loaded into T7‐CMNVs, and biodistribution experiments indicated that T7‐CMNVs delivered AMO21c more efficiently into the brain than CMNVs, scrambled T7‐CMNVs, lipofectamine, and naked AMO21c after systemic administration. In addition, AMO21c down‐regulated miRNA‐21 (miR‐21) levels in glioblastoma tissue most efficiently in the T7‐CMNVs group. This enhanced suppression of miR‐21 resulted in the up‐regulation of PDCD4 and PTEN. Eventually, brain tumor size was reduced in the T7‐CMNVs group more efficiently than in the other control groups. With stability, low toxicity, and targeting efficiency, T7‐CMNVs may be useful to the development of oligonucleotide therapy for brain tumors.

Cervical cancer stem cells (CCSCs) represent a subpopulation of tumor cells that possess self-renewal capacity and numerous intrinsic mechanisms of resistance to conventional chemotherapy and radiotherapy. These cells play a crucial role in relapse and metastasis of cervical cancer. Therefore, eradication of CCSCs is the primary objective in cervical cancer therapy. Salinomycin (Sal) is an agent used for the elimination of cancer stem cells (CSCs); however, the occurrence of several side effects hinders its application. Nanoscale drug-delivery systems offer great promise for the diagnosis and treatment of tumors. These systems can be used to reduce the side effects of Sal and improve clinical benefit. Sal-loaded polyethylene glycol-peptide-polycaprolactone nanoparticles (Sal NPs) were fabricated under mild and non-toxic conditions. The real-time biodistribution of Sal NPs was investigated through non-invasive near-infrared fluorescent imaging. The efficacy of tumor growth inhibition by Sal NPs was evaluated using tumor xenografts in nude mice. Flow cytometry, immunohistochemistry, and Western blotting were used to detect the apoptosis of CSCs after treatment with Sal NPs. Immunohistochemistry and Western blotting were used to examine epithelial-mesenchymal transition (epithelial interstitial transformation) signal-related molecules. Sal NPs exhibited antitumor efficacy against cervical cancers by inducing apoptosis of CCSCs and inhibiting the epithelial-mesenchymal transition pathway. Besides, tumor pieces resected from Sal NP-treated mice showed decreased reseeding ability and growth speed, further demonstrating the significant inhibitory ability of Sal NPs against CSCs. Moreover, owing to targeted delivery based on the gelatinase-responsive strategy, Sal NPs was more effective and tolerable than free Sal. To the best of our knowledge, this is the first study to show that CCSC-targeted Sal NPs provide a potential approach to selectively target and efficiently eradicate CCSCs. This renders them a promising strategy to improve the therapeutic effect against cervical cancer.

The protective blood‐brain barrier (BBB) prevents most therapeutic agents from entering the brain. Currently, focused ultrasound (FUS) is mostly employed to create microbubbles that induce a cavitation effect to open the BBB. However, microbubbles pass quickly through brain microvessels, substantially limiting the cavitation effect. Here, we constructed a novel perfluoropropane‐loaded microbubble, termed ApoER‐Pep‐MB, which possessed a siloxane bonds‐crosslinked surface to increase the microbubble stability against turbulence in blood circulation and was decorated with binding peptide for apolipoprotein E receptor (ApoER‐Pep). The microbubble with tailor‐made micron size (2 µm) and negative surface charge (−30 mV) performed ApoER‐mediated binding rather than internalization into brain capillary endothelial cells. Consequently, the microbubble accumulated on the brain microvessels, based on which even a low‐energy ultrasound with less safety risk than FUS, herein diagnostic ultrasound (DUS), could create a strong cavitation effect to open the BBB. Evans Blue and immunofluorescence staining studies demonstrated that the DUS‐triggered cavitation effect not only temporarily opened the BBB for 2 h but also caused negligible damage to the brain tissue. Therefore, various agents, ranging from small molecules to nanoscale objects, can be efficiently delivered to target regions of the brain, offering tremendous opportunities for the treatment of brain diseases. A novel microbubble decorated with ApoER‐Pep for specific binding to the low‐density lipoprotein receptors predominantly expressed on brain microvessels is constructed. This strategy greatly boosted the diagnostic ultrasound‐elicited cavitation effect of microbubbles on the wall of brain microvessels while significantly reducing side effects for opening the blood‐brain barrier, which provided tremendous opportunities for testing varisized therapeutic/diagnostic agents against brain diseases.