The success of messenger RNA therapeutics largely depends on the availability of delivery systems that enable the safe, effective and stable translation of genetic material into functional proteins. Here we show that extracellular vesicles (EVs) produced via cellular nanoporation from human dermal fibroblasts, and encapsulating mRNA encoding for extracellular-matrix α1 type-I collagen (COL1A1) induced the formation of collagen-protein grafts and reduced wrinkle formation in the collagen-depleted dermal tissue of mice with photoaged skin. We also show that the intradermal delivery of the mRNA-loaded EVs via a microneedle array led to the prolonged and more uniform synthesis and replacement of collagen in the dermis of the animals. The intradermal delivery of EV-based COL1A1 mRNA may make for an effective protein-replacement therapy for the treatment of photoaged skin.Recent developments in messenger RNA-modification techniques have enhanced the therapeutic efficiency of mRNA delivery and its potential for near-term clinical applications, including protein-replacement therapy and vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus 1,2 . However, the intrinsic inability and potential immunogenicity of mRNAs require that they be encapsulated within delivery vehicles. Current mRNA-delivery modalities centre on the usage of lipid nanoparticle (LNP) carriers for encapsulation and

Triple‐negative breast cancer (TNBC) is the most lethal subtypes of breast cancer. Although chemotherapy is considered the most effective strategy for TNBC, most chemotherapeutics in current use are cytotoxic, meaning they target antiproliferative activity but do not inhibit tumor cell metastasis. Here, a TNBC‐specific targeted liposomal formulation of epalrestat (EPS) and doxorubicin (DOX) with synergistic effects on both tumor cell proliferation and metastasis is described. These liposomes are biocompatible and effectively target tumor cells owing to hyaluronic acid (HA) modification on their surface. This active targeting, mediated by CD44‐HA interaction, allows DOX and EPS to be delivered simultaneously to tumor cells in vivo, where they suppress not only TNBC tumor growth and the epithelial‐mesenchymal transition, but also cancer stem cells, which collectively suppress tumor growth and metastasis of TNBC and may also act to prevent relapse of TNBC.

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Even though chemotherapy regimens for treating cancer by inducing apoptosis are extensively utilized, their therapeutic effect is hindered by multiple limitations. Thus, a combination of other types of anticancer modalities is urgently needed. Herein, a tannic acid (TA)-Fe 3+ -coated doxorubicin (DOX)-encapsulated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (ammonium salt) (DSPE-PEG) micelle (TFDD) for apoptosis/ferroptosis-mediated immunogenic cell death (ICD) is reported. By coating TA-Fe 3+ on the surface of DOX-loaded micelles, an apoptotic agent and a ferroptotic agent are simultaneously delivered into the cancer cells and induce cell death. Furthermore, the intracellular oxidative environment generated by the apoptosis/ferroptosis hybrid pathway stimulates the endoplasmic reticulum (ER) and leads to ICD induction. The in vivo results show that the combination treatment of TFDD and anti-programmed death-ligand 1 antibodies (anti-PD-L1) considerably inhibits tumor growth and improves antitumor immunity by activating CD4 + and CD8 + T cells and decreasing the ratio of regulatory T cells (Treg) to CD4 + T cells. This study suggests that the apoptosis/ferroptosis-mediated ICD inducer may offer a potent strategy for enhanced cancer immunotherapy.

Antigen delivery through an oral route requires overcoming multiple challenges, including gastrointestinal enzymes, mucus, and epithelial tight junctions. Although each barrier has a crucial role in determining the final efficiency of the oral vaccination, transcytosis of antigens through follicle-associated epithelium (FAE) represents a major challenge. Most of the research is focused on delivering an antigen to the M-cell for FAE transcytosis because M-cells can easily transport the antigen from the luminal site. However, the fact is that the M-cell population is less than 1% of the total gastrointestinal cells, and most of the oral vaccines have failed to show any effect in clinical trials. To challenge the current dogma of M-cell targeting, in this study, we designed a novel tandem peptide with a FAE-targeting peptide at the front position and a cell-penetrating peptide at the back position. The tandem peptide was attached to a smart delivery system, which overcomes the enzymatic barrier and the mucosal barrier. The result showed that the engineered system could target the FAE (enterocytes and M-cells) and successfully penetrate the enterocytes to reach the dendritic cells located at the subepithelium dome. There was successful maturation and activation of dendritic cells in vitro confirmed by a significant increase in maturation markers such as CD40, CD86, presentation marker MHC I, and proinflammatory cytokines (TNF-α, IL-6, and IL-10). The in vivo results showed a high production of CD4+ T-lymphocytes (helper T-cell) and a significantly higher production of CD8+ T-lymphocytes (killer T-cell). Finally, the production of mucosal immunity (IgA) in the trachea, intestine, and fecal extracts and systemic immunity (IgG, IgG1, and IgG2a) was successfully confirmed. To the best of our knowledge, this is the first study that designed a novel tandem peptide to target the FAE, which includes M-cells and enterocytes rather than M-cell targeting and showed that a significant induction of both the mucosal and systemic immune response was achieved compared to M-cell targeting.