Ischemic heart disease and related sequelae pose tremendous burdens on worldwide medical care. The excessive activation of cardiomyocytes and cardiac fibroblasts further exacerbates the prognosis after necrosis. Decades of stem cell therapy in preclinical studies suggested promising results in cardiomyocyte regeneration and tissue remodeling. However, few formulations achieved clinical translation due to the limited stem cell engraftment and insufficient arousal of resident cardiomyocytes. Here, we reported an implantable electroactive device to leverage stem cell therapy and cardiomyocyte restoration for effective heart recovery. Assisted by the piezoelectric microneedle patch with 80-cubic millimeter cavity, 1.5 × 105 mesenchymal stem cells could be delivered efficiently to the infarcted site and sustained longer for continuous paracrine effects. Meanwhile, the piezoelectric stimulation generated from the poly(l-lactic) acid microneedle matrix further potentiated the stem cells and elicited more vigorous self-repair responses in cardiomyocytes. This approach was validated to effectively suppress inflammatory monocytes, reduce cardiomyocyte necrosis, and improve heart remodeling in a rat heart infarction model.

The molecular-level co-doping of organic-inorganic components yields unique hybrid materials, which are constrained by their inherent interfacial incompatibility causing expulsion of organic phases from inorganics. Inspired by the occlusion of organic phases within inorganic single crystals, we engineer an intracrystalline-penetrating organic-inorganic hybrid structure to convert biomass DNA into bulk bio-geological materials. Specifically, we utilize calcium phosphate oligomers (CPOs) as inorganic molecules to chemically bond with DNA’s backbone, subsequently initiating inorganic crosslinking cascades to prepare bulk DNA minerals with long-range ordered mineralized networks, in which DNA is penetrated within the crystalline phase of hydroxyapatite (HAP). The intracrystalline-penetrating architecture confers exceptional mechanical reinforcement to DNA minerals with the modulus of 14.8 GPa. The tunable DNA-HAP hybrid ratio enables stability modulation of DNA minerals, rendering them viable as biodegradable materials. Consequently, DNA minerals can serve as recyclable bioplastics, information storage materials, and bone regeneration scaffolds, merging tailored stability with different application requirements.

Mitochondrial transplantation is a promising therapeutic approach involving the transfer of exogenous mitochondria into diseased cells to restore impaired mitochondrial homeostasis. However, its clinical translation is severely limited by the lack of efficient methods for precise and potent mitochondria transfer. Inspired by natural mitochondria-containing vesicles, we develop mesenchymal stem cell-derived biomimetic nanovesicles with high mitochondrial loading capacity and augmented extracellular mitochondrial stability. These nanovesicles exhibit an ability to efficiently and selectively deliver mitochondrial cargo to injured cells, which is potentially ascribed to the specific interaction between very late antigen-5 on the nanovesicle surface and pathologically upregulated fibronectin on injured cells. In a mouse pulmonary fibrosis model, these nanovesicles successfully deliver healthy mitochondria to injured lung epithelial cells through airway administration, resulting in a significant reduction in fibrotic progression. This study introduces a design of mitochondria-enriched biomimetic nanovesicles for effective and targeted mitochondria transfer, offering a nanotechnology-based strategy to advance mitochondrial transplantation therapy.

Advances at the intersection of biotechnology, artificial intelligence, electronics and materials science are reshaping how drugs can be delivered inside the body. Intelligent and miniaturized drug delivery devices (IMDDDs) leverage these technologies to achieve precise pharmacokinetics, targeted distribution and programmable release while minimizing toxicity and improving patient adherence. Unlike conventional approaches, IMDDDs can incorporate real-time sensing and adaptive control, enabling drug administration that is more precise and more responsive to dynamic physiological conditions. In this Review, we outline key categories and design principles, highlight artificial intelligence technologies for augmenting performance, discuss potential clinical applications across cancer, diabetes, cardiovascular disease, vaccination and beyond, and examine translation challenges and opportunities. By uniting engineering innovation with medical need, IMDDDs exemplify the next generation of drug delivery technologies.

Adoptive cell therapy (ACT), exemplified by the success of chimeric antigen receptor (CAR)-T cells in treating hematologic malignancies, has transformed oncology by enabling precise elimination of cancer cells. Here, we report an alternative paradigm of ACT: adoptive transfer of platelets pre-infected with oncolytic viruses (OVs) for metastasis treatment. Platelets, beyond their role in hemostasis, possess the ability to selectively recognize and bind circulating tumor cells (CTCs) via the CD62p/CD44 and Clec-2/podoplanin pathways, forming platelet-tumor cell aggregates that induce platelets activation. Once activated, platelets can deliver OVs toward CTCs through various mechanisms, including platelet microparticles, intercellular transport via intracellular component exchange, or direct viral release, thereby facilitating tumor cell infection and lysis to inhibit metastasis. This strategy exhibited potent anti-metastatic efficacy in preclinical mouse models of melanoma, breast, and colon cancer. Furthermore, we demonstrated that a short-term platelet depletion prior to adoptive platelet transfusion can potentiate therapeutic outcomes.

To address the core limitations of conventional insulin therapy,including delayed glycemic control and the frequent risk of hypoglycemia,the development of glucose-responsive insulin delivery systems capable of dynamically sensing blood glucose levels and releasing insulin on demand has emerged as a pivotal strategy.Based on their underlying sensing mechanisms,these systems are generally classified into three categories:those utilizing glucose oxidase,glucose-binding molecules,and phenylboronic acid.From the perspective of administration routes,injectable and transdermal delivery are the two primary approaches for glucose-responsive insulin.Injectable glucose-responsive insulin delivery systems are highly compatible with existing clinical practices,primarily relying on glucose-responsive carriers to regulate the insulin release rate and achieve stable and efficient bioavailability.Transdermal glucose-responsive insulin delivery systems utilize glucose-responsive microneedle arrays to penetrate the skin stratum corneum and precisely control the rate of insulin release,allowing for sufficient insulin delivery under almost painless conditions.This review systematically summarizes recent advances in both injectable and transdermal glucose-responsive insulin delivery systems,with a focus on carrier design strategies,glucose-responsive release mechanisms,and evolutionary pathways of preparation techniques.It also highlights the contributions of these systems toward improved glucose-responsiveness,therapeutic safety,biocompatibility,and patient adherence.Furthermore,challenges and future prospects for clinical translation are discussed.This overview is expected to provide valuable insights for further research and development in this field.

Abstract Cell-based drug delivery uses living cells’ advantages, including prolonged circulation, tissue tropism, barrier crossing, and immune compatibility, to improve drug biodistribution, prolong exposure, and enhance efficacy with reduced toxicity. Genetic engineering approaches like CAR-T therapy, while transformative, face significant hurdles, such as genomic risks, immune toxicities like cytokine release syndrome, strict regulations, expensive GMP manufacturing, and lengthy production timelines. These issues have spurred interest in nongenetic strategies that maintain native cell functions through intracellular loading methods (endocytosis, hypotonic loading, physical poration, cell–liposome fusion) and membrane modifications (covalent and noncovalent conjugation). This Review examines the mechanisms, trade-offs, and compatibility of these approaches with various carrier cells such as erythrocytes, platelets, macrophages, neutrophils, T cells, and NK cells. It further discusses key translational challenges, including safety, immunogenicity, donor and batch heterogeneity, manufacturing, cryopreservation, regulatory standardization, and progression from preclinical to clinical stages.

Controlling the self-assembly of mesoporous materials beyond equilibrium remains a fundamental challenge. Conventional templating systems form ordered structures through energy-minimizing coassembly but lack the kinetic and spatial freedom required to produce asymmetric or topologically complex architectures. Here, we report a bioinspired coacervate-directed silicification strategy that enables diffusion-limited and spatially asymmetric condensation within soft templates, yielding ordered hexagonal mesoporous nanotoroids. In this system, poly(acrylic acid) (PAA) electrostatically associates with the cationic surfactant cetyltrimethylammonium bromide (CTAB), driving liquid-liquid phase separation and forming disc-like coacervate assemblies. Reaction-diffusion imbalance across the inner and outer interfaces within these templates induces asymmetric silicification, driving an interior collapse and toroidal self-transformation. By tuning PAA concentration, the diffusion-condensation kinetics can be precisely modulated, allowing programmable control over collapse dynamics and final topology, with enlarged central cavities (14-71 nm) and reduced rim thickness (15-35 nm). These nanotoroids exhibit uniform sub-100 nm size, high surface area (846 m2 g-1), and abundant mesopores (∼2.0 nm). The nanotoroids (rim thickness ∼15 nm, height ∼40 nm) display markedly prolonged blood circulation, enhanced tumor accumulation (+173%), improved vascular extravasation, and deeper intratumoral penetration, while reducing hepatic and splenic uptake by 19% and 14%, respectively, compared with spherical analogues. These combined advantages translate into potent antitumor efficacy in both subcutaneous and spinal metastasis models. This work establishes a new paradigm for sol-gel topology control by bridging reaction-diffusion dynamics with bioinspired silicification based on the chemistry of LLPS (liquid-liquid phase separation), thereby unlocking the untapped biomedical potential of toroidal topologies that were rarely accessible.

Cancer stem-like cells contribute to innate tumour immunoresistance and an immunosuppressive tumour microenvironment, leading to poor responses to immune checkpoint inhibitors. Chemotherapeutic agents can elicit tumour immunogenicity by inducing immunogenic cell death to reinforce the therapeutic efficacies of immune checkpoint inhibitors, but suffer from inefficient immunogenic cell death activation in highly resistant cancer stem-like cells. Here we report an immunostimulatory lyotropic liquid-crystal-based lipogel for localized co-delivery of all-trans retinoic acid, a differentiation-inducing drug, and doxorubicin, an immunogenic-cell-death-inducing chemotherapeutic agent with distinct release kinetics. The lipogel is tailored to release the combinatorial drugs in a differential and sustained manner, which fulfils the requirement for enhanced drug synergism in promoting the immunogenic cell death of cancer stem-like cells. Local implantation of the immunostimulatory lipogel elicits an antitumour immune response that is further augmented by an immune checkpoint inhibitor to suppress tumour growth and metastasis, as well as to prevent post-surgical recurrence in murine models of high-stemness tumours.

Successful treatment of resectable intestinal diseases hinges on advanced intestinal anastomosis techniques and effective postoperative management. However, current postoperative adjuvant therapy remains limited to systemic administration of medications after conventional hand-sewn anastomosis, frequently leading to associated complications and potential recurrence. Here, we introduce a microneedle anastomotic stent (MAS) for postoperative intestinal healing and localized drug delivery in resectable intestinal diseases. This MAS integrates a biodegradable polyglycolic acid stent with a stimulus-responsive polyprodrug microneedle patch. This design provides robust mechanical properties, effective prevention of anastomotic leakage, and on-demand drug release at the anastomotic site. After intestinal resection, the MAS is implanted at the anastomotic site, where the microneedles penetrate the mucosal layer and release the anti-inflammatory drug in response to hyperinflammatory conditions, thereby attenuating local inflammation and facilitating anastomotic healing. In vitro assays verified the minimal cytotoxicity and good biocompatibility of the MAS and its degradation products. The efficacy of the MAS in tissue penetration and stimulus-responsive drug release was demonstrated using ex vivo patient samples. The in vivo therapeutic benefit and mechanism of the MAS were validated in the murine radiation colitis model, and its feasibility and safety were further confirmed in the minipig model of ischemic inflammatory injury. The MAS also exhibited versatility as a delivery platform for diverse therapeutics, suggesting potential applications in complex intestinal diseases. Compared with conventional methods, in preclinical studies, the MAS offered a sutureless approach for intestinal anastomosis and postoperative adjuvant therapy, holding potential for treating various resectable intestinal diseases.

Stem cell therapy has demonstrated significant therapeutic potential. However, the relatively large cellular diameter increases the likelihood of entrapment within capillaries, impeding the migration of stem cells to disease foci. We, herein, propose an enucleation strategy to enhance cell deformability, significantly improving vascular transit efficiency. Computational modeling, combined with experimental investigations using a microfluidic platform, revealed that increased cellular deformability, rather than a reduction in diameter, plays a greater role in facilitating cell transit, thereby challenging traditional perspectives on the cell mechanics. Observations of pulmonary vasculature using optical tissue-clearing and fluorescence micro-optical sectioning tomography confirmed the extensive distribution of enucleated cells and their reduced entrapment within fibrotic foci. Consequently, enucleated mesenchymal stem cells could efficiently deliver mRNAs to the fibrotic sites, significantly mitigating pulmonary fibrosis. Our findings provide new insights into the role of enucleation in facilitating cellular transit through constricted vasculature and the underlying mechanobiology of enhanced deformability.

Accumulating evidence indicates that platelets promote cancer progression through direct interactions with malignant cells, the secretion of soluble mediators and the release of platelet-derived extracellular vesicles. In certain contexts, platelets can also suppress tumour progression by modulating immune responses, delivering antiproliferative microRNAs or releasing inhibitory factors. This dynamic and context-dependent interplay limits the effectiveness of strategies that solely inhibit or activate platelet activity and has driven the development of engineering approaches to reprogramme platelets with therapeutic intent. Unlike most cellular products, platelet-based approaches can be implemented in both autologous and allogeneic settings, providing more flexible approaches for developing new therapies. Over the past few years, advances in genetic and chemical engineering have enabled the multifunctional modification of platelets while preserving native properties essential for cancer therapy. Engineered platelets can act as targeted delivery vehicles to enhance local drug accumulation and release, or as active effector cells that directly modulate tumour progression. The clinical implementation of these engineered products will require control of platelet stability and activation, scalable manufacturing processes and rigorous safety evaluation. In this Review, we summarize the current understanding of platelet biology in cancer, examine engineering strategies for their therapeutic use, and outline opportunities and challenges for their clinical translation.

Cutaneous melanoma, characterized by high recurrence, metastasis, and mortality rates, necessitates early diagnosis to improve patient survival. Current methods for melanoma screening, primarily dermoscopy and skin biopsies, face critical limitations: dermoscopy often sacrifices sensitivity, while biopsy requires invasive tissue removal, compromising patient compliance. Here, we present a minimally invasive microneedle-based device for early melanoma detection through interstitial fluid (ISF) analysis. The device consists of a vacuum extraction system for ISF extraction, a fluid reservoir for storing chromogenic solution, and a lyophilized gelatin hydrogel for lactate dehydrogenase sensing. The detection capability of the device is validated both in vitro and in vivo in a melanoma-bearing mice model. The device successfully distinguishes melanoma-bearing mice from healthy controls at early stage, without influencing tumor progression. This minimally invasive and visually readable device offers a patient-friendly alternative to traditional invasive procedures for melanoma screening.

Against the escalating global threat of antibiotic resistance, phages have emerged as a promising biological therapy capable of selectively lysing pathogenic bacteria. However, their rapid systemic clearance and limited tissue targeting remain major obstacles to clinical translation. Here, we develop platelet-phage conjugates (PPCs) as a biologically guided delivery platform to enhance targeted phage therapy for bacterial pneumonia. By harnessing the innate inflammatory tropism of platelets, phages are conjugated onto platelet carriers, enabling active homing to sites of infection. As early responders to inflammatory cues, platelets rapidly accumulate at infectious foci, where they sequester bacteria and facilitate microbial clearance. Leveraging these intrinsic properties, PPCs achieve precise localization within infected lung tissue. Meanwhile, the infection environment and the direct bacterial interactions also trigger platelet activation and platelet-derived microparticles release, promoting the localized release of conjugated phages. We demonstrate that PPCs significantly increased accumulation in lung infection regions, extend their circulation half-life, and effectively treat pneumonia in mice caused by bacterial infections.

Oncolytic adenoviruses (OVs) can directly eliminate cancer cells and subsequently activate immune responses, exhibiting potent antitumor therapeutics. However, it was observed that the immune cells can also be lysed during viral treatment, evidently dampening the OVs-mediated antitumor immune response. In this study, we develop a microneedle (MN)-based in situ tumor cell-derived extracellular nanovesicle (TDEV)-cloaked OVs platform to enhance cancer immunotherapy and reduce immune cell exhaustion. In this platform, tumor cells pre-infected with OVs are loaded into the upper reservoir of the MN device. Following the transdermal administration, the hollow MN would constantly facilitate the transport of in situ the generated TDEV-encapsulating OVs into the tumor site for sustained delivery of OVs, which could subsequently infect cancer cells selectively rather than immune cells. Enhanced antigens triggered by improved intratumoral OVs killing can be presented by non-exhausted dendritic cells, further evoking significant immunotherapeutic effects in both TC-1-hCD46 xenograft tumor-bearing mice and postoperative tumor recurrence mice models.

BACKGROUND & AIMS:The immune-inflammatory cascade is a dominant process mediating allograft inflammatory injury and rejection, thereby threatening the survival of both allografts and recipients. However, the primary driver of this progression remains unclear, and targeted intervention remains a critical challenge in the development of effective treatments. METHODS:Bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) analyses were employed to elucidate the key mechanisms underlying allograft inflammatory injury and rejection. Subsequently, a platelet-based drug delivery platform was developed to mitigate allograft inflammatory injury. RESULTS:Chemokine C-C motif ligand 2 (CCL2) was identified as a key molecule involved in early allograft dysfunction in clinical cohorts. CCL2 was persistently expressed in monocytes during the first post-transplant week, promoting monocyte infiltration, which led to inflammatory injury and subsequent rejection through cellular crosstalk with adaptive immune cells. Platelets accumulated in the allograft and exhibited excellent delivery efficiency. A platelet-based delivery system was engineered to interrupt CCL2-CCR2 signaling. Specifically, anti-CCL2 antibodies were covalently conjugated to the surface of platelets (PLT-aCCL2). In both ischemia-reperfusion injury and orthotopic liver transplantation models, a single intravenous injection of PLT-aCCL2 attenuated CCR2+ monocyte infiltration, thereby suppressing liver inflammatory injury and alleviating acute allograft rejection. scRNA-seq revealed that PLT-aCCL2 reconfigured the immune landscape of the liver allograft by disrupting myeloid-T cell crosstalk. CONCLUSIONS:CCL2-CCR2 signaling is a key driver of early inflammatory injury and a critical link connecting this process with subsequent cellular rejection. Anti-CCL2-conjugated platelets, with high drug-loading efficiency, biocompatibility, and allograft-targeting capability, offer a promising therapeutic strategy for protecting liver allografts. IMPACT AND IMPLICATIONS:This study demonstrates that CCL2, through dynamic interactions with CCR2+ monocytes, is a key driver of acute inflammatory injury and contributes to subsequent cellular rejection, supported by multi-omics data from both clinical liver transplantation (LT) cohorts and an orthotopic LT mouse model. For the first time, we show that platelets can deliver anti-CCL2 antibodies to the liver allograft, thereby disrupting the immune-inflammatory cascade driven by CCL2-CCR2+ monocyte signaling and protecting liver function during acute inflammation. We further demonstrate that PLT-aCCL2 alleviates acute cellular rejection by reducing interactions between myeloid cells and T cells, particularly between monocytes and CD8+ cytotoxic T cells.

Preventing cancer recurrence after surgical removal, while preserving breast cosmesis and restoring function, remains challenging. Traditional scaffold-based approaches are often restricted by their inadequate integration with natural tissues and unmatched rate of material degradation to tissue development. Here we report an anticancer drug secretion system based on engineered mammary organoids for inhibiting post-surgical tumour recurrence and promoting tissue reconstruction. By inducing the lactation of mammary organoids, cytoplasmic lipid droplets form intracellularly. A pH-responsive prodrug, comprising all-trans retinal and the chemotherapeutic agent doxorubicin, is readily encapsulated in these lipid droplets. Upon lactation, milk fat globules, enriched with these drug-loaded lipid droplets, are released to residual tumour cells through the contractile actions of myoepithelial cells. Both mouse and human-induced pluripotent stem cell-derived mammary organoids were engineered as drug-secreting depots and demonstrated their effectiveness in inhibiting tumour recurrence (96% regression) in a mouse post-surgical breast cancer model. In addition, the organoids could be self-adaptively integrated with mammary glands and contribute to their reconstruction, ultimately restoring lactational capacity in the recipient mice.

Zheng Su, Zhicheng Le and Zhen Gu introduce the Nanoscale Advances themed issue on Nanoscale Advances in Innovative Bioengineering.

Tumor-targeted delivery of oncolytic viruses (OVs) via systemic administration could not only expand virotherapy beyond primary tumors to widespread metastases, but also improve clinical adherence and convenience. We here engineer megakaryocytes encapsulating oncolytic adenovirus type 5 (M-Ad5) to produce oncolytic platelets in vivo by leveraging the thrombopoiesis process. Upon intravenous administration, M-Ad5 travels through the lungs, where it can release OVs-harbored therapeutic platelets into circulation under pulmonary turbulence microenvironments. Under the shelter of platelets, OVs resist inactivation by neutralizing antibodies and actively target widespread noninjectable cancer lesions. Intravenous infusion of M-Ad5 to mice with A549 lung cancer could significantly inhibit tumor growth and prolong survival. In multiple mouse tumor models, M-Ad5 induced a robust antitumor immune response by reprogramming the immunosuppressive tumor microenvironment, and potentiated the response to immune checkpoint inhibitors by recruiting more immune cells. We demonstrated that M-Ad5 in combination with PDL1 inhibitors activated tumor antigen-specific CD8(+) T cells and memory T cells, thereby suppressing the growth of CT26 colorectal cancer metastasis, and preventing postsurgical B16F10 cancer recurrence and metastatic spread, as well as providing long-term immune protection against the rechallenged tumors.

Despite the promise of DNA base editors for diverse genome editing applications, their utility remains constrained by off-target effects, which are exacerbated by short spacers in miniature systems and the large size of Cas9-derived editors, which impedes adeno-associated virus (AAV) delivery. Here, guided by structural insights into a compact Cas9d nuclease from Deltaproteobacteria, we developed an efficient Cas9d system (Cas9dUltra) through gRNA and protein engineering, and further developed its base editors (9dBEs). Cas9dUltra and 9dBEs enabled efficient and precise genome editing in human cells. Notably, 9dCBE induced premature termination codons in 89% of mouse pups by microinjection, facilitating robust disease modeling. Furthermore, a single AAV delivering 9dCBE achieved efficient Pcsk9 editing and a concomitant reduction in serum LDL-C levels in mice. Collectively, this study establishes a series of compact, potent genome editing tools poised to advance biological and biomedical translational research.