Yunfeng Lin

Burn wound repair requires not only rapid wound closure but also coordinated regulation of the evolving pathological processes across distinct healing stages to minimize scar formation. However, many existing wound dressings address only isolated aspects of healing and are often limited by burst release, short local retention, and insufficient intracellular delivery. Here, we report ATMP@Gel, a GelMA hydrogel incorporating an activatable tetrahedral miR‐146a‐5p nanoprodrug (ATMP), for multistage regulation of burn wound repair. The tetrahedral nanoframework improves miRNA stability and cellular uptake, while the hydrogel matrix prolongs local delivery; RNase H‐responsive activation further contributes to increasing the functionally available intracellular pool of miR‐146a‐5p. ATMP@Gel attenuates excessive inflammation and oxidative stress during early repair, shifts the macrophage marker profile toward a reparative state, and suppresses fibroblast overactivation and profibrotic remodeling at later stages of healing. In a murine full‐thickness burn model, ATMP@Gel accelerates wound closure and promotes angiogenesis, re‐epithelialization, restoration of skin appendage structures, and more normal‐like collagen architecture, while reducing residual scar area and scar‐associated fibrosis. Together, these findings demonstrate a miRNA nanoprodrug hydrogel strategy that integrates sustained local delivery with responsive intracellular regulation to coordinate multiple pathological processes throughout burn wound healing.

Cancer drug resistance, a major cause of chemotherapy failure, arises from multiple interconnected barriers, including reduced intracellular drug accumulation, enhanced drug efflux, adaptive survival signaling, increased DNA repair, and redox or metabolic remodeling. To address these limitations, recent advances in programmable DNA nanostructures have provided new opportunities for constructing multifunctional nanotherapeutic platforms. This review examines how the structural characteristics of DNA nanostructures influence drug delivery, molecular regulation, and resistance modulation, and analyzes how different DNA nanoplatforms, including tetrahedral framework nucleic acids, DNA origami, DNA nanoflowers, spherical nucleic acids, and hybrid DNA assemblies, contribute to therapeutic regulation. It then highlights their applications in overcoming major resistance‐associated barriers, such as inefficient cellular uptake, drug efflux, apoptosis evasion, DNA repair activation, and biochemical adaptation. Finally, it discusses the challenges in DNA nanostructure‐based cancer therapy and proposes future directions for improving stability, intracellular delivery, tumor accumulation, immune safety, and scalable manufacturing. These advances suggest that DNA nanostructures may serve as next‐generation programmable nanomedicine platforms for multilevel intervention against cancer drug resistance.

Precise theranostics requires spatiotemporal control and high specificity to adapt to complex physiological microenvironments. Tetrahedral framework nucleic acids (tFNA), classic 3D DNA nanostructures, offer distinct advantages such as atomic-level structural precision, intrinsic programmability, and excellent biocompatibility. While traditional static tFNA lack dynamic responsiveness to external stimuli─severely limiting their clinical translation potential─the emergence of dynamically responsive tFNA has garnered increasing attention. These smart systems offer substantial advantages, including stimulus-triggered structural reconfiguration, targeted payload release, and real-time signal transduction. Despite rapid design innovations, a systematic summary of dynamic tFNA strategies remains lacking. Accordingly, we synthesize the design principles of responsive tFNA by categorizing their mechanisms into conformational rearrangement, chemical bond cleavage, and toehold-mediated strand displacement logic. We highlight their applications in precision diagnosis, smart therapeutics, and theranostics integration and discuss critical challenges in biological stability, scalable manufacturing, and biosecurity. By mapping current advancements and unresolved hurdles, this work provides a comprehensive reference for the rational design of responsive DNA nanodevices and discusses the challenges associated with the clinical translation of dynamic tFNA.

Immune rejection is a major challenge for the long-term survival of allogeneic skin grafts. Current immunosuppressive therapies are usually administered systemically to mitigate rejection; however, they have substantial side effects. Therefore, here, a localized immunomodulatory strategy based on tetrahedral framework nucleic acids (tFNAs) is proposed to improve the survival of allogeneic skin grafts. A mircoRNA (miR-23b) and a dendritic cell-targeting aptamer is conjugated to tFNAs to create a complex (termed TR), which is embedded in a four-armed PEG hydrogel (MixPEG) matrix to form MixPEG-TR. TR targets dendritic cells (DCs) in the skin to induce tolerogenic DCs by leveraging the transdermal delivery capability of tFNAs and the sustained release provided by the hydrogel, thereby establishing persistent local immune tolerance. The local application of this formulation reduces inflammatory cell infiltration, promotes uniform dermal collagen deposition, and markedly prolongs graft survival in a mouse allogeneic skin graft model. These findings highlight a transdermal, DC-targeted nucleic acid delivery strategy capable of enhancing local immune tolerance and alleviating inflammatory responses, thereby potentially maintaining graft-associated immune homeostasis and providing a safer, site-specific platform for immunomodulation in skin transplantation and other cutaneous immune-mediated conditions.

Fibrosis is both a consequence and a driving factor of intervertebral disc degeneration (IVDD); however, the origins, pathways, and regulatory mechanisms of fibrotic effector cells remain incompletely understood, complicating antifibrotic therapy development. In this study, we identified pericytes as novel fibrotic effector cells in IVDD, contributing to fibrosis through activation of the TGF‐β signaling pathway. To address this, we developed a microgel platform (MMS@TRP) designed to specifically inhibit pericyte activation and pro‐fibrotic transition. MMS@TRP was constructed by integrating a tetrahedral framework nucleic acid (tFNA)‐based nanocarrier (TRP), which encapsulates a miR‐21 inhibitor and is conjugated with a pericyte‐targeting peptide (pPB), onto tannic acid (TA)‐based metal‐phenolic network (MPN)‐functionalized gelatin methacryloyl microspheres (GelMA MS). This microgel system protects TRP from enzymatic degradation by nucleases while facilitating its pH‐sensitive release. The early‐stage release of TRP from MMS@TRP ensures targeted delivery of the miR‐21 inhibitor to pericytes, suppressing pericyte proliferation, migration, and myofibroblast transition by blocking the TGF‐β signaling pathway. Simultaneously, sustained TA release provides prolonged protection to nucleus pulposus cells (NPCs) through reactive oxygen species (ROS) scavenging, mitochondrial preservation, and anti‐inflammatory effects. Collectively, the MMS@TRP platform presents a versatile and innovative approach for mitigating IVDD by inhibiting fibrosis and protecting NPCs.