Chemotherapy remains central to oral squamous cell carcinoma (OSCC) management but is constrained by poor specificity, systemic toxicity, multidrug resistance, and limited durability. Tumor-derived exosomes (TEX) offer a clinically relevant carrier owing to their biocompatibility, low immunogenicity, and homotypic targeting; however, prevailing high-efficiency loading methods (electroporation/sonication/extrusion, etc.) may disrupt membrane proteins, promote cargo leakage and aggregation, and increase costs—hindering clinical translation. Here we report IR808/Doxorubicin@Tumor-derived Exosomes (ID-TEX) that combine endogenous IR808 loading (preserving membrane integrity and homotypic ligands) at cell level with covalent, pH-responsive anchoring of doxorubicin via a hydrazone linker on the exosome surface (HYD-DOX). Upon cellular uptake, acidification in endosomes/lysosomes rapidly cleaves the linker, releasing DOX to induce nuclear DNA damage, followed by IR808-mediated photodynamic therapy (PDT) to amplify oxidative stress—establishing a sequenced chemo-PDT cascade. Leveraging the native integrin repertoire and CD47 signaling of TEX, ID-TEX achieves active homing, prolonged circulation, uniform intratumoral distribution, and deep penetration. Mechanistically, the intensified oxidative and multi-pathway cytotoxic stress elicits immunogenic cell death (ICD), promotes dendritic cell maturation, and recruits CD8⁺ and CD4⁺ T cells, converting “cold” OSCC into “hot” tumors and transforming localized photochemotherapy into systemic antitumor immunity. Centering this chemo-photodynamic–immunotherapeutic cascade on enhanced ROS, ID-TEX concurrently improves efficacy, reduces toxicity, and strengthens immune modulation, underscoring strong translational potential for precision OSCC therapy.

Compared to hematologic malignancies, solid tumors respond poorly to immunotherapy, largely due to their immunosuppressive microenvironment and lack of effective immune regulatory molecules. Signaling Lymphocyte Activation Molecule Family Member 7 (SLAMF7), a macrophage-activating receptor highly expressed in hematologic cancers, is scarcely present in solid tumors. While tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) possess anti-tumor potential, their phagocytic capacity remains untapped in solid tumors. We herein developed a glutathione (GSH)-responsive nanoparticle platform based on PLGA10k-S-S-mPEG5k to deliver plasmid DNA encoding SLAMF7 (NPpSLAMF7) into solid tumor cells. Successful SLAMF7 expression effectively reprogrammed these cells to mimic hematopoietic cancer cells, thereby inducing potent macrophage phagocytosis. RNA-seq and KEGG pathway analysis revealed that upon phagocytosis, macrophages activated phagocytosis-related and cytokine-cytokine receptor interaction pathways, leading to increased secretion of CXCL9 and CXCL10, driving CD8+ T cell recruitment. In both orthotopic and metastatic breast tumor models, NPpSLAMF7 synergized with anti-PD-1 antibody therapy, achieving maximal tumor suppression. Our work establishes NPpSLAMF7 as the first nanoplatform to induce SLAMF7 expression in solid tumors, thereby enhancing macrophage-mediated phagocytosis and CD8+ T cell infiltration. This strategy reprograms the TME and acts synergistically with PD-1 blockade, offering a promising strategy for next-generation solid tumor immunotherapy.

Liver pre-metastatic niches (PMN) formation is a pivotal process in colorectal cancer liver metastasis (CLM). Phosphatase of regenerating liver-3 (PRL-3) has been demonstrated as a key factor in promoting CRC progression (e.g., therapeutic resistance and metastasis), but its role in liver PMN formation remains unknown. Using mouse models and CRC patient samples, we herein reveal that high PRL-3 expression in CRC cells could enhance the recruitment of myeloid-derived suppressor cells (MDSCs) into the liver and impair the hepatic infiltration of CD8+ T cells, thereby promoting the liver PMN formation and CLM. Mechanistically, high PRL-3 expression could activate the Src/STAT3 signaling pathway in CRC cells and thus up-regulate integrin αvβ5 (ITGαvβ5) expression in their secreted exosomes, which could specifically target F4/80+ macrophages in the liver to activate the P38/STAT1 signaling pathway. With this activation of P38/STAT1 pathway, the secretion of C-X-C motif chemokine ligand 12 (CXCL12) from F4/80+ macrophages is significantly improved, which could enhance the recruitment of MDSCs into the liver and impair the hepatic infiltration of CD8+ T cells, ultimately leading to the liver PMN formation and CLM. Taken together, our findings not only uncover the important role of PRL-3 in CLM via promoting the liver PMN formation, but also provide the evidence for the treatment of CLM by targeting PRL-3.

Activation of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-interferon gene stimulator (STING) pathway has demonstrated significant potential in cancer treatment due to its crucial role in bridging the innate and adaptive immunity. However, clinical attempts of current cGAS-STING activating approaches remain challenged because of their undesired adverse effects and low therapeutic efficacy. We herein developed a new and robust immunostimulatory RNA interfering (RNAi) nanoplatform to potentiate breast cancer (BCa) immunotherapy through precise activation of cGAS-STING pathway and effective immune checkpoint blockade. This nanoplatform comprises the electrostatic complexes of small interfering RNA (siRNA) targeting oncogene coactivator-associated arginine methyltransferase 1 (Carm1) and metformin prodrug. Using orthotopic and metastatic BCa tumors, we demonstrated this nanoplatform could suppress the proliferation of BCa cells via siRNA-mediated Carm1 silencing and down-regulate programmed death-ligand 1 (PD-L1) expression via metformin-mediated ubiquitin-proteasome degradation. More importantly, due to the important role of oncogene Carm1 in repairing damaged double stand DNA (dsDNA), Carm1 silencing could specifically enhance the accumulation of damaged dsDNA and cytosolic release of dsDNA fragments to precisely activate the cGAS-STING pathway in BCa cells, which could thus promote their expression and secretion of interferon-β (IFN-β) to induce a significant inhibition of BCa tumor growth via leveraging both the innate and adaptive immunity.

Background:Immune checkpoint inhibitor (ICI) therapies have marked a significant breakthrough in tumor immunotherapy. However, their clinical efficacy remains suboptimal in many cases. Emerging evidence indicates that resistance to ICIs is largely driven by the immunosuppressive nature of the tumor microenvironment (TME). Modulating the TME-through conventional chemotherapy or anti-angiogenic therapies has been shown to enhance immune activation and improve the therapeutic response to ICIs. Methods:In this study, we developed epirubicin (EPI)-loaded lipid nanoparticles, termed DPPA(EPI) LNPs, which integrate the chemotherapeutic agent EPI with the anti-angiogenic lipid DPPA, enabling co-delivery and targeted enrichment within tumors. The cytotoxicity and anti-vascular endothelial cell tube formation properties of DPPA(EPI) LNPs were tested in vitro. The biosafety, anti-tumor ability and immunoactivities were tested on orthotopic tumor models of both breast cancer and hepatoma in vivo. Results:DPPA(EPI) LNPs showed the advantages of uniformed particle size, high stability, good sustained-release effect. Compared to free drug, DPPA(EPI) LNPs significantly prolonged blood circulation (21.7% remaining at 12 h vs.16.5% at 30 min for free drug), enhanced tumor accumulation (18.4-fold change than free drug) and had well biological safety. In vivo, DPPA (EPI) LNPs showed excellent anti-tumor therapeutic efficacy by significantly inhibiting tumor cell proliferation (Ki67† cells reduced by 55%), reducing tumor angiogenesis (vascular density by 60%), and inducing stronger immunogenic cell death effect both in 4T1 orthotopic tumor model and Hepa1-6 orthotopic tumor model. And the treatment of DPPA (EPI) LNPs combined with programmed cell death protein 1 (PD-1) inhibitor further improved the activation of anti-tumor immunity in the TME, which leads to more significant inhibition of the tumor growth. Conclusion:This dual-function nanoplatform-combining chemotherapy and anti-angiogenic therapy-substantially improved the efficacy of PD-1 blockade in both breast cancer and hepatocellular carcinoma (HCC) models. These findings offer a promising strategy and experimental foundation for TME modulation and the advancement of combination immunotherapy.

Abnormal lipid metabolism plays an important role in the development and progression of almost all cancer types, especially hepatocellular carcinoma (HCC) as the liver is the central organ for lipid storage and metabolism. However, the underlying mechanisms are complex and have not been completely elucidated. By analyzing the proteomic sequencing and single cell RNA-sequencing (scRNA-seq) results of HCC patients, we herein reveal that acyl-CoA synthase long chain family member 3 (ACSL3) is predominately expressed in HCC cells and high ACSL3 expression is positively correlated with abnormal lipid metabolism and predicts the poor prognosis of HCC patients. Mechanically, ACSL3 could promote the synthesis of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), which could activate peroxisome proliferator-activated receptor α (PPARα) pathway and enhance the transcription of downstream lipid metabolism-associated genes, thereby promoting HCC growth and metastasis via accelerating lipid catabolism and anabolism. Considering the lack of specific inhibitor for ACSL3, we further develop an endosomal pH-responsive nanoparticle (NP) platform for systemic delivery of ACSL3 siRNA (siACSL3) and demonstrate its ability to inhibit HCC tumor growth and metastasis. Our findings indicate that ACSL3 could be used to predict the prognosis of HCC patients and NPs-mediated ACSL3 silencing could be a promising strategy for effective HCC therapy.

Breast cancer remains the most frequently diagnosed malignancy among women, accounting for over 30 ​% of all cancer cases in this population. Although the incorporation of targeted therapies has significantly improved clinical outcomes, therapeutic resistance and immune evasion continue to undermine durable disease control. Myeloid cells—including monocytes, macrophages, dendritic cells (DCs), and granulocytes—play a pivotal role in orchestrating the tumor microenvironment (TME). While these cells exhibit immunostimulatory properties under physiological conditions, they often adopt immunosuppressive and pro-tumorigenic phenotypes within the TME, thereby facilitating tumor progression, metastasis, and resistance to treatment. Nanomedicine has emerged as a promising platform for modulating the TME, offering enhanced delivery precision, controlled drug release, and the potential to reprogram immune responses. In particular, nanoparticle-based systems—including liposomes, polymeric nanoparticle (PNP), micelles, and hybrid nanomaterials—have been actively investigated for their capacity to selectively target and manipulate myeloid cell populations in breast cancer. By delivering immunomodulatory agents directly to these cells, such strategies aim to reverse their tumor-supportive functions and reinvigorate anti-tumor immunity. This review provides a comprehensive overview of recent advances in nanomedicine-based approaches for targeting myeloid cells in breast cancer.We discuss the underlying biological mechanisms, preclinical efficacy, and translational challenges—including nanoparticle stability, specificity, and scalability—that must be addressed to facilitate clinical implementation. Integrating nanotechnology with immunomodulation represents a promising frontier in precision oncology, with the potential to overcome therapeutic resistance and improve outcomes in breast cancer management.

Tumor microenvironment (TME) is the major obstacle in cancer immunotherapy due to its adverse effects on tumor-infiltrating immune cells. Emerging evidences have revealed that mitophagy plays an important role in regulating cell fate and immune microenvironment. Targeted regulation of mitophagy could be a promising strategy for enhanced cancer immunotherapy, which however remains unexploited due to the absence of robust therapeutic platform. We herein developed a mitophagy-induced RNA interfering (RNAi) nanoplatform composed of a hydrophilic polyethylene glycol (PEG) shell and an endosomal pH-responsive hydrophobic core encapsulating the complexes of mitophagy-inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and small interfering RNA (siRNA) for enhanced breast cancer (BCa) immunotherapy. Using the orthotopic and metastatic BCa tumor models, we demonstrate that this nanoplatform could effectively induce excessive mitophagy in BCa cells to suppress their proliferation and silence PD-L1 expression to block its immunosuppressive effect on CD8+T cells. More importantly, excessive mitophagy could inhibit CC motif chemokine ligand 2 (CCL2) secretion from BCa cells and thus alleviate the immunosuppressive effect on CD8+T cells via impairing the tumor infiltration of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which could ultimately combine with the PD-L1 silencing to synergistically enhance the antitumor immunity and inhibit BCa tumor growth. STATEMENT OF SIGNIFICANCE: Amplification of mitophagy in tumor cells has been considered as a promising strategy for effective cancer therapy due to its important role in regulating cell fate and TME. We herein developed a mitophagy-induced RNAi nanoplatform, which could effectively induce BCa cell death via amplifying mitophagy and enhance the tumoricidal ability of CD8+T cells via silencing PD-L1 expression. More importantly, this nanoplatform-induced excessive mitophagy could inhibit tumor-derived CCL2 secretion and thus remodel the immunosuppressive TME via impairing the tumor infiltration of TAMs, Tregs, and MDSCs, leading to enhanced antitumor immunity and significant inhibition of BCa tumor growth. The nanoplatform developed herein could be used as an effective tool for enhanced cancer immunotherapy.

Rationale: Sonodynamic therapy (SDT) has emerged as a promising non-invasive modality with deeper tissue penetration than photodynamic or chemodynamic therapies. However, its therapeutic efficacy remains limited due to inadequate reactive oxygen species (ROS) generation, largely attributed to tumor-intrinsic antioxidant systems and mitophagy. Existing combinations of SDT with immunotherapy are primarily additive and fail to address the mechanistic interplay between ROS suppression and immune evasion. Methods: To overcome these limitations, we developed a redox-responsive RNA interference (RNAi) nanoplatform (NP) for the co-delivery of Nrf2 siRNA, the mitophagy inhibitor 3-Methyladenine (3-MA), and the sonosensitizer purpurin-18 (P-18). This NP enables tumor-specific release in high-glutathione environments and facilitates dual-pathway inhibition upon ultrasound activation. Results: This synergistic platform simultaneously disrupted Nrf2-mediated antioxidant defenses and mitophagy-dependent mitochondrial clearance, resulting in enhanced intracellular ROS accumulation. Elevated ROS levels triggered immunogenic cell death (ICD), promoting dendritic cells maturation and antigen presentation. Concurrently, 3-MA inhibited NF-κB signaling, downregulating PD-L1 expression and mitigating T cell exhaustion. In murine breast cancer models, this dual-action approach elicited robust CD8⁺ T cell responses and significantly suppressed tumor growth and metastasis. Conclusions: This study introduces a mechanistically integrated sonoimmunotherapeutic strategy that concurrently overcomes ROS suppression and immune checkpoint resistance. By orchestrating redox disruption and immune reprogramming, our nanoplatform provides a compelling framework for next-generation SDT-based immunotherapy.

Breast cancer remains the most prevalent malignancy among women worldwide, with triple-negative breast cancer (TNBC) representing its most aggressive and lethal subtype. TNBC is characterized by high rates of recurrence and lung metastasis after surgery, severely impacting patient quality of life. Recent studies highlight the critical role of metabolic reprogramming in driving cancer recurrence, migration, and invasion. While the underlying mechanisms remain complex and not fully elucidated, transcriptomic analyses comparing primary and metastatic breast cancer tissues from TNBC and Luminal patients have identified lysophosphatidylcholine acyltransferase 1 (LPCAT1) as a key enzyme upregulated in lung metastases and TNBC. LPCAT1 is strongly associated with poor prognosis due to its activation of the TGFβ signaling pathway. This activation is driven by LPCAT1's ability to increase cellular ATP levels, fostering a high-energy state that stimulates ATPase activity. Consequently, ATP-dependent chromatin remodeling via the BAF complex, which includes double PHD finger 2 (DPF2) as a critical subunit, regulates gene transcription essential for tumor progression. Through the LPCAT1-DPF2-TGFBR2 axis, TNBC cells enhance TGFβ signaling, promoting malignant behavior and metastasis. Addressing this, we developed a reduction-responsive nanoparticle platform for the systemic delivery of LPCAT1-targeted siRNA (siLPCAT1), which has shown significant efficacy in suppressing TNBC tumor growth and metastasis. These findings suggest that nanoparticle-mediated siLPCAT1 delivery represents a promising therapeutic strategy for advanced TNBC treatment.

BACKGROUND:Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by "self" immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different populations of B cells, particularly in the early stages of T1D, has not been fully elucidated. METHODS:In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to investigate immune cell populations in patients with newly diagnosed T1D, their relative controls and age-matched healthy controls. Phosphoprotein microarray analysis was employed to investigate changes in protein phosphorylation in B cells. Furthermore, we developed a siRNA-based nanomedicine and evaluated its therapeutic potential in the NOD mouse. The integration of scRNA-seq, flow cytometry, phosphoprotein microarrays, and functional assays established a robust framework for understanding and targeting B cell-mediated autoimmunity in T1D. FINDINGS:Using single-cell RNA sequencing, we discovered that patients with T1D exhibited increased humoural immunity in the early stage of T1D. Specifically, the population of naïve B cells increased in patients with newly diagnosed T1D who expressed elevated levels of the AKT kinase coactivator TCL1A. Using a protein phosphorylation microarray, we confirmed that TCL1A knockdown specifically impaired AKT2 phosphorylation and affected B cell survival and proliferation. Notably, we discovered that the naïve B cell population increased and TCL1A expression was upregulated in NOD mice that developed T1D. Both the levels of naïve B cells and TCL1A were strongly associated with glucose intolerance in T1D mice. Importantly, treatment with a siRNA-based nanomedicine targeting Tcl1a mRNA effectively reduced the number of naïve B cells, prevented the loss of pancreatic β cells, and improved glucose intolerance in T1D mice. INTERPRETATION:Using single-cell RNA-seq, we have not only uncovered a naïve B cell specific gene that may contribute to the pathogenesis of T1D but also highlighted the potential of siRNA-based nanomedicine for treating T1D. The clinical translation of these findings offers a new approach for the treatment of T1D. FUNDING:See Acknowledgements.

Immune checkpoint blockade (ICB) therapy has become the first-line treatment for cancer patients. However, the low response rate remains a clinical pain-point. Anti-hyperglycemic drug metformin has shown remarkable anticancer effect with the unique characteristic of modulating tumor immune microenvironment (TIME). Therefore, combining ICB with metformin could be a promising strategy for enhanced cancer immunotherapy, which however remains challenged due to the low bioavailability and severe adverse effects of metformin. This work herein designs an amphiphilic reduction-responsive metformin prodrug, which could complex small interfering RNA (siRNA) and then co-assemble with an endosomal pH-responsive PEGylated polymer to form a dual-responsive immunomodulatory RNAi nanoplatform. Using the orthotopic and metastatic breast cancer (BCa) tumor models, this work demonstrates that this RNAi nanoplatform could silence PD-L1 expression on BCa cells and suppress their proliferation via activating AMP-activated protein kinase (AMPK). Moreover, this AMPK activation could suppress the secretion of tumor-derived transforming growth factor β (TGF-β) and interleukin 6 (IL-6), which could enhance the maturation of dendritic cells (DCs) and activation of CD8+ T cells and impair the tumor infiltration of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), ultimately achieving the goal of enhanced cancer immunotherapy and significant inhibition of BCa tumor growth.

Pancreatic ductal adenocarcinoma (PDAC) represents 90 % of pancreatic cancers and shows limited response to immune therapy owing to the highly immunosuppressive tumor microenvironment (TME). Cytokine-encoded mRNA therapy demonstrates a great promise in converting "cold" tumors into "hot" ones, while it is typically administered through intratumoral injection and applicable only to superficial tumors, which limites their application in PDAC. In this study, we design and develop a lipid nanoparticle (LNP) delivery system capable of targeting pancreatic tissue via intraperitoneal (I.P.) injection. This system not only efficiently delivers mRNA to pancreatic tissues but also selectively targets immune cells in PDAC. A single I.P. injection of LNP encapsulating interleukin-12 (IL-12) mRNA (LNP/mIL-12) activates both myeloid and lymphoid cells in PDAC, reprogramming the immunosuppressive TME. Remarkably, I.P. injection of LNP/mIL-12 induces eradication of orthotopic PDAC in some cases. Our work represents the first relatively non-invasive method to deliver IL-12 mRNA for targeted treatment of orthotopic PDAC, offering a novel approach for PDAC immunotherapy.

Neoadjuvant chemotherapy has been widely used for the treatment of solid tumors. However, clinical observations have shown that patients with oral squamous cell carcinoma (OSCC) who are receiving neoadjuvant chemotherapy with cisplatin still face issues such as a poor lymph node response and even lymph node progression, but the underlying mechanisms remain unidentified. In this work, it is found that low-dose cisplatin promoted oral squamous cell carcinoma migration, invasion and lymph node metastasis, and gasdermin D (GSDMD) is identified as a potential regulator. GSDMD interacted with MMP14, promoting its expression and epithelial‒mesenchymal transition (EMT) activation without activating pyroptosis. Moreover, pH-responsive nanoparticles (NPs) for the systemic delivery of a GSDMD siRNA (siGSDMD) is developed and showed that this NP-delivered siGSDMD can effectively inhibit OSCC tumor growth and metastasis via the efficient silencing of GSDMD expression in vivo. This findings indicate that GSDMD can be a biomarker to predict the prognosis of OSCC patients receiving neoadjuvant chemotherapy and that NP-mediated GSDMD silencing can be a promising strategy for the treatment of patients with advanced OSCC receiving neoadjuvant chemotherapy with cisplatin.

Chemotherapy remains the primary treatment modality for breast cancer (BCa) patients. However, chemoresistance commonly arises in clinical settings, contributing to poor prognosis. The development of chemoresistance is a dynamic and complex process involving the activation of oncogenes and inactivation of tumor suppressor genes. In this work, we utilized the RNA-sequencing (RNA-seq) technology to analyze the gene expression profiles of primary and recurrent tumor samples from BCa patients received the postoperative standard chemotherapy with doxorubicin (DOX), and identified glutathione S-transferase P1 (GSTP1) as a key factor in regulating chemoresistance. Molecular mechanistic studies revealed that high GSTP1 expression could not only impair the cytotoxicity of DOX by catalyzing the conjugation of reductive glutathione (GSH) with DOX, but also block the c-Jun NH2-terminal kinase (JNK) pathway to promote the proliferation via up-regulating anti-apoptotic B-cell lymphoma-2 (Bcl-2) expression. Given the severe side effects of DOX and the potential of RNA interference (RNAi) technology to silence target gene expression, we developed an endosomal pH-responsive nanoparticle (NP) platform for systemic co-delivery of DOX and GSTP1 siRNA (siGSTP1), and demonstrated its efficacy in reversing chemoresistance and suppressing the growth of DOX-resistant BCa tumors.

Hepatocellular carcinoma (HCC) progression and therapy sensitivity are critically fueled by liver cancer stem cells (LCSCs), yet the regulatory mechanisms of circular RNAs (circRNAs) on LCSCs remain elusive. Here, through circRNA microarray analysis of LCSCs and non-stem HCC cells, circRAPGEF1 is identified as a LCSC-enriched circRNA upregulated in HCC tissues and predictive of poor patient survival. Functionally, circRAPGEF1 promoted the stemness properties, proliferation, and tumorigenicity of HCC cells. Mechanistically, the METTL3-mediated N6-methyladenosine (m6A) modification of circRAPGEF1 facilitated KH domain-dependent binding of IGF2BP3 to its UGGAC motif, which conferring stability to circRAPGEF1 while competitively disrupting the IGF2BP3/ASS1 mRNA interaction. This process led to the degradation of ASS1 mRNA, triggering aspartate accumulation and activation of the S6K/CAD signaling pathway. Crucially, circRAPGEF1 overexpression reduced the sorafenib sensitivity, whereas targeting circRAPGEF1 using nanoparticles-mediated systematic siRNAs delivery effectively sensitized HCC cells to sorafenib. Collectively, these findings unveil a METTL3/circRAPGEF1/IGF2BP3/ASS1 regulatory axis that drives aspartate metabolic reprogramming to fuel HCC stemness properties, positioning circRAPGEF1 as a dual prognostic biomarker and therapeutic target to enhance sorafenib efficacy in HCC.

Messenger RNA (mRNA) therapy has been applied to the treatment of various human diseases including malignant tumors. Increasing evidences have shown that mRNA can enhance the efficacy of cancer immunotherapy by modulating the functions of immune cells and stimulating their activity. However, mRNA is a type of negatively charged biomacromolecules that are susceptible to serum nucleases and cannot readily cross the cell membrane. In the past few decades, various nanoparticles (NPs)-based delivery systems have been rationally designed and developed to facilitate the intracellular uptake and cytosolic delivery of mRNA. More importantly, by means of the specific recognition between the targeting ligands decorated on NP surface and receptors specifically expressed on immune cells, these mRNA delivery systems could be functionalized to target immune cells to further enhance the mRNA-based cancer immunotherapy. In this review, we briefly introduced the advancements of mRNA in cancer therapy, discussed the challenges faced by mRNA delivery, and systematically summarized the recent development in NPs-based mRNA delivery systems targeting various types of immune cells for cancer immunotherapy. The future development of NPs-mediated targeted mRNA delivery and their challenges in clinical translation are also discussed.

Extracellular vesicles (EVs) are emerging as promising carriers for the delivery of therapeutic biologics. Genetic engineering represents a robust strategy for loading proteins of interest into EVs. Identification of EV‐enriched proteins facilitates protein cargo loading efficiency. Many EV‐enriched proteins are sorted into EVs via an endosomal sorting complex required for transport (ESCRT)‐dependent pathway. In parallel, viruses hijack this EV biosynthesis machinery via conserved late domain motifs to promote egress from host cells. Inspired by the similarity of biogenesis between EVs and viruses, we developed a synthetic, Late domain‐based EV scaffold protein that enables the display of a set of single chain variable fragments (scFvs) on the EV surface. We named this scaffold the Late domain‐based exosomal antibody surface display platform (LEAP). We applied the LEAP scaffold to reprogramme HEK293T cell‐derived EVs to elicit T‐cell anti‐tumor immunity by simultaneously displaying αPD‐L1 and αCD3 scFvs on the EV surface (denoted as αPD‐L1×αCD3 bispecific T‐cell engaging exosomes, BiTExos). We demonstrated that αPD‐L1×αCD3 BiTExos actively redirected T cells to bind to PD‐L1+ tumor cells, promoting T‐cell activation, proliferation and tumoricidal cytokine production. Furthermore, the αPD‐L1×αCD3 BiTExos promoted T‐cell infiltration into the tumor microenvironment to mitigate the tumor burden in vivo. Our study suggested that the LEAP scaffold may serve as a platform for EV surface display and could be applied for a broad range of EV‐based biomedical applications.