Mohammad Mahdi Hasani‐Sadrabadi

Autoimmune diseases encompass a diverse group of disorders with distinct clinical manifestations but a unifying defect, the breakdown of immune self-tolerance that drives dysregulated immune activation. Current therapies broadly suppress immunity rather than reestablishing regulatory balance and therefore provide limited and often transient control. Building on recent advances in nanomedicine, we introduce an immunoengineering framework that restores immune balance by delivering antigens, co-signals, and tissue repair cues with spatial and temporal precision. This review systematically examines synthetic (liposomes, polymeric nanoparticles, 2D materials), biologically derived and bioinspired (extracellular vesicles, bacterial/viral and cell-membrane vesicles), and hybrid systems, outlining design rules including size and shape, surface chemistry and ligand valency, cargo architecture, and stimuli responsiveness, that govern biodistribution, cellular uptake, and immune programming. Mechanistic principles are illustrated across distinct contexts (e.g., alloantigen responses, mucosal barrier failure, β-cell autoimmunity), emphasizing strategies that induce antigen-specific tolerance, reprogram innate compartments, and repair barriers while preserving protective immunity. We also map key translational needs: standardized characterization and potency assays, long-term safety and biodistribution, scalable manufacturing, regulatory fit, and cost-effectiveness. Together, these insights provide a blueprint for precision nanomedicine to move autoimmunity treatment from blanket suppression toward durable, mechanism-based remission.

Photoactivated drug delivery is a promising therapeutic strategy that enables spatial and temporal control of payload release. A critical component of this approach is the photoresponsive material that has sufficient drug-loading capacity and can be actuated by near-infrared (NIR) light with considerable penetration depths. Here, we establish a photoactivated drug delivery platform based on the π-stacked organic framework (πOF), which demonstrates an intrinsic NIR absorption and superior photothermal effect. πOF not only has considerable loading capacity for a variety of drugs but also prompts the inducible burst release of loaded cargoes under NIR irradiation with notable increase of the release rate. Based on these features, πOF is used to effectively modulate the delivery of resiquimod (R848) and simultaneously induce photothermal effect by NIR irradiation. In 4T1-bearing mouse models, the photoactivated release of R848 can significantly potentiate treatment efficacy.

Embryos can achieve immune tolerance, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), secrete extracellular vesicles (EVs) that markedly outperform mesenchymal stem cell (MSC)–derived EVs in suppressing pro-inflammatory cytokine secretion, inhibiting activated T-cell proliferation, and inducing regulatory T-cell (Treg) formation through CDK8 downregulation. Nuclear magnetic resonance (NMR) analysis reveals distinct molecular fingerprints of PSC EVs compared to those of MSC EVs. Moreover, comparative analyses show that PSC EVs contain unique proteins and microRNAs, such as the pluripotency-associated proteins ROR1 and CD133 and members of the miR-302 family, which are not found in MSC EVs, as determined by proteomic profiling and microRNA sequencing. Notably, the dynamic suspension culture of PSC aggregates significantly increases EV yield, offering a scalable and reproducible source superior to other cell sources. To evaluate their therapeutic potential, we employed an antigen-specific type 1 diabetes model and found that two local injections of iPSC EVs, particularly when delivered via a biomaterial scaffold, significantly enhanced diabetes-free survival. These treatments increased Treg populations in draining lymph nodes, induced systemic immunomodulation, and preserved β-cell mass from immune-mediated destruction. The immunomodulatory capability of PSC EVs suggests broad applications in treating autoimmune diseases and supporting stem cell-derived cell therapies by promoting immune tolerance. Their scalability, consistency, and superior therapeutic properties position PSC EVs as a compelling platform for next-generation immunotherapies and cell-based treatment strategies.

The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8+ T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy. Synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells provide substantial enhancements in the expansion and potency of engineered human cytotoxic T cells.

Abstract Periodontitis is initiated by dysbiosis of the oral microbiome. Pathogenic bacteria elicit ineffective immune responses, which damage surrounding tissues and lead to chronic inflammation. Although current treatments typically aim for microbial eradication, they fail to address the significance of immune cell reactions in disease progression. Here, we searched for small molecules as drug candidates and identified a bifunctional antibiotic, azithromycin (AZM), that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation. We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues. Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro. In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration. In addition, microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles, had similar or slightly enhanced therapeutic outcomes respectively. The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents, providing a practical and streamlined approach for clinical treatment. Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation. Graphical Abstract

The durability of a protective immune response generated by a vaccine depends on its ability to induce long-term T cell immunity, which tends to decline in aging populations. The longest protection appears to arise from T memory stem cells (TMSCs) that confer high expandability and effector functions when challenged. Here we engineered artificial antigen presenting cells (aAPC) with optimized size, stiffness and activation signals to induce human and mouse CD8 + TMSCs in vitro . This platform was optimized as a vaccine booster of TMSCs (Vax-T) with prolonged release of small-molecule blockade of the glycogen synthase kinase-3β together with target antigens. By using SARS-CoV-2 antigen as a model, we show that a single injection of Vax-T induces durable antigen-specific CD8 + TMSCs in young and aged mice, and generates humoral responses at a level stronger than or similar to soluble vaccines. This Vax-T approach can boost long-term immunity to fight infectious diseases, cancer, and other diseases.

One of the main challenges in tissue engineering is finding a way to deliver specific growth factors (GFs) with precise spatiotemporal control over their presentation. Here, we report a novel strategy for generating microscale carriers with enhanced affinity for high content loading suitable for the sustained and localized delivery of GFs. Our developed microparticles can be injected locally and sustainably release encapsulated growth factors for up to 28 days. Fine-tuning of particles' size, affinity, microstructures, and release kinetics is achieved using a microfluidic system along with bioconjugation techniques. We also describe an innovative 3D micromixer platform to control the formation of core-shell particles based on superaffinity using a polymer-peptide conjugate for further tuning of release kinetics and delayed degradation. Chitosan shells block the burst release of encapsulated GFs and enable their sustained delivery for up to 10 days. The matched release profiles and degradation provide the local tissues with biomimetic, developmental-biologic-compatible signals to maximize regenerative effects. The versatility of this approach is verified using three different therapeutic proteins, including human bone morphogenetic protein-2 (rhBMP-2), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1α). As in vivo morphogenesis is typically driven by the combined action of several growth factors, the proposed technique can be developed to generate a library of GF-loaded particles with designated release profiles.

Here, we developed a stromal cell-derived factor-1a (SDF-1α) delivery biomaterial as an artificial polymeric-based niche with the ability to recruit local endogenous human gingival mesenchymal stem cells (hGMSCs) for craniofacial bone regeneration applications. Polydopamine-coated poly(ε-caprolactone) (PCL)-gelatin electrospun membranes were loaded with stromal cell-derived factor-1α (SDF-1α) via physical adsorption. Subsequently, the release profile of SDF-1α and the chemotactic capacity on human bone marrow mesenchymal stem cells (hBMMSCs) and hGMSCs were evaluated. The osteogenic differentiation capacity of the recruited MSCs was also assessed in vitro . Our results confirmed the sustainable release of SDF-1α from the developed biomaterial promoting the migration and homing of human bone marrow mesenchymal stem cells (hBMMSCs) and hGMSCs. Moreover, the results of the osteogenic differentiation assay showed that SDF-1α delivery significantly enhanced osteogenic differentiation of hBMMSCs and hGMSCs and up-regulated the gene expression of osteogenic markers compared to the control group. In conclusion, the current study successfully developed a novel and effective treatment modality for craniofacial bone regeneration by recruiting the autogenous progenitor cells including hGMSCs. The developed niches can potentially lead to the development of a novel platform for targeted manipulation of in vivo microenvironment to achieve efficient and safe craniofacial cell reprogramming, which also will pave the road to determine the capacity of local hGMSCs' contribution to in situ bone regeneration.

Zhang et al.1 show that the mechanical properties of a three-dimensional (3D) hydrogel can enhance the secretion of niche factors from bone marrow stromal cells, which in turn promotes the maintenance of hematopoietic stem cells (HSCs) and reverses aging hallmarks in HSCs.