The importance of mechanotransduction as a key regulator of immune-cell function has grown, linking the tissue microenvironment to cell phenotype, activity, and response to therapy. Mechanobiology and stimuli-responsive biomaterials are converging to become a new approach to precision immunomodulation, the focus of this review. The roles of matrix stiffness, viscoelasticity, confinement, and nanoscale topography in sensing by integrins, focal-adhesion complexes, Piezo1, YAP/TAZ and nuclear mechanotransduction by LINC complexes, and their influence on cytoskeletal organization, transcriptional programs, and immune-cell function, are described. We then explore how macrophages, dendritic cells, T cells, neutrophils, monocytes, and regulatory immune cells combine these mechanical signals with biochemical signaling. We focus on stiffness-tunable, stress-relaxing, adaptive, self-healing, and architecture biomaterials, as well as magnetic, electrical, photonic, acoustic, and multi-stimuli-responsive platforms. They are evaluated for therapeutic roles in cancer immunotherapy, chronic inflammation, wound healing, fibrosis, infection and foreign body-associated responses. Lastly, we discuss barriers to translation, including biological heterogeneity, dosimetry, biosafety, manufacturing, and regulatory challenges, as well as new opportunities based on artificial intelligence, digital twins, real-time sensing, and closed-loop control. Together, these advances establish biomaterials as programmable interfaces that can dynamically integrate mechanical and biochemical cues to orchestrate and achieve a spatio-temporally precise immune regulation.
Nanomaterials have been present for centuries as colloidal materials in historical objects such as Lycurgus Cup, medieval church windows and weapons made of Damascus steel. However, it was until Turkevich designed a controlled synthesis method for metallic nanomaterials (MNMs), specifically gold nanoparticles. Nowadays, many methods have been proposed for the preparation or synthesis of MNMs relying on two approaches: top-down and bottom-up. Physical methods rely on the former as they often turn macroscopic material into a nanometric one. These methods are relatively simple, scalable and offer high purity materials, but require large amounts of energy and specific equipment. On the other hand, chemical methods rely on bottom-up approaches, requiring only a precursor salt for the preparation of MNMs along with a reducing agent for the formation of nanomaterials. Chemical methods are versatile regarding equipment, generate more stable nanomaterials and have more control of the product’s size and shape. However, they are characterized by low purity and use of toxic solvents. Due to the environmental impact of these methods, biogenic synthesis has been proposed as an alternative bottom-up method, analogous with chemical synthesis but utilizing biological resources from plants, algae, bacteria, among others as reducing agents to form stable MNMs. Although these methods have their own disadvantages, they utilize renewable resources, are safer, and have comparable physicochemical properties. This review will mainly focus on i. the main biogenic synthesis methods of MNMs, ii. biological resources involved in these methods and iii. the properties of the obtained nanomaterials compared to the MNMs synthesized by conventional methods.
IntroductionThe present study focused on evaluating the anticancer potential of biosynthesized Trachyspermum ammi-mediated silver nanoparticles (TA-AgNPs) using both in vitro and in vivo approaches.MethodologyTA-AgNPs were synthesized through a rapid, eco-friendly, and cost-effective green synthesis method and assessed for their suitability in biomedical applications. In vitro anticancer activity was examined against the A431 epidermal skin cancer cell line using the Alamar Blue assay. In vivo anticancer activity was evaluated using a two-stage skin carcinogenesis model induced by 7,12-dimethylbenz [a]-anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) in Swiss albino mice. Various tumor parameters, including tumor incidences, tumor yield, tumor burden, tumor size, and average latent period, were assessed. Additionally, antioxidant status was analyzed through superoxide dismutase (SOD) activity. This was further supported by histopathological analysis and estimation of serum interleukin-6 (IL-6) levels.Results and DiscussionTA-AgNPs demonstrated dose-dependent cytotoxic activity against A431 skin cancer cells in vitro (2.5–25 μg/mL). In vivo, TA-AgNPs treatment markedly reduced tumor incidence, yield, and burden while delaying tumor onset compared to the carcinogen control (Group I: 181.6 pg/mg), with the continuous treatment (Group IIc) providing the most pronounced protection. TA-AgNPs enhanced antioxidant defense, with Group IIc showing a highly significant elevation in SOD activity (55.41 U/50 µL) compared to Groups IIa (45.22 U/50 µL) and IIb (43.34 U/50 µL). Serum IL-6 levels remained elevated across carcinogen-treated groups (Group I: 181.6 pg/mg; Groups IIa–IIc: 162.8–198.5 pg/mg) compared to untreated baseline controls (63.5 pg/mg), reflecting the persistent pro-inflammatory microenvironment established during DMBA/TPA-mediated tumorigenesis. Importantly, TA-AgNPs administered alone (Group III: 65.2 pg/mg) caused no significant IL-6 elevation, demonstrating their baseline biocompatibility and lack of inherent immunogenicity. Histopathology confirmed preserved epithelial architecture in TA-AgNP-treated groups. These findings indicate that TA-AgNPs exert potent chemopreventive effects primarily through antioxidant enhancement and direct tumor growth mitigation rather than systemic IL-6 suppression.
Successful organ repair requires more than the delivery of a structurally supportive scaffold to the site of injury. Tissue injury establishes a self-propagating microenvironment where oxidative stress and inflammation reciprocally reinforce each other, causing degradation of implanted materials, inactivation of bioactive cargo, and spread of damage to surrounding healthy tissue. This pathological cycle questions the basic assumption of conventional scaffold design, where mechanical support is considered sufficient and the host microenvironment passive. Rather, a larger body of evidence suggests that the scaffold is an active participant in the injury response, one that can scavenge reactive oxygen species (ROS), restore redox homeostasis, and re-direct inflammation toward resolution rather than chronicity. This review synthesizes the design rationale, bioactive ingredients, and matrix platforms underpinning this emerging class of antioxidant and anti-inflammatory biohybrid materials, with particular emphasis on extracellular vesicle (EV)-loaded constructs, natural-extract systems, endogenous-agent biohybrids, and surface-modified or stimuli-responsive matrices, which can be programmed to release in spatiotemporal fashion. The current analysis argues that the ROS-NF-kB-Nrf2 axis represents the major, but underutilized, opportunity in the field and evaluates each construct class with respect to this coupling, rather than in isolation, in contrast to previous reviews, which treat antioxidant and anti-inflammatory approaches as parallel design paths. The evidence supporting these strategies for cardiac, hepatic, renal, neural, and cutaneous repair is critically evaluated, along with the preclinical models employed to validate them and the manufacturing, regulatory, and clinical-translation hurdles that currently limit their application. The principal obstacles to clinical deployment, rather than any deficit in mechanistic rationale, are identified as persistent gaps: irreproducible potency assays, animal models that poorly represent the aged and comorbid patients most in need of therapy, and unresolved trade-offs between payload protection and bioactivity. The review concludes that next-generation regenerative biomaterials for pathologically stressed organs will require biomimetic matrices engineered for precise spatiotemporal control over both antioxidant and immunomodulatory functions and that achieving this will depend less on the discovery of new bioactive agents than on solving the integration, standardization, and validation challenges that currently separate promising constructs from clinical practice.
Circular RNAs (circRNAs) are covalently closed RNA molecules with exceptional intrinsic stability and when properly designed, purified, nucleoside-modified, and delivered, show reduced unwanted innate immune activation, endowing them with unique advantages for vaccines, cancer immunotherapy, and protein replacement therapies. Synthetic circRNAs can be generated via enzymatic ligation, chemical ligation, or ribozyme-mediated circularization; however, efficient translation and scalable manufacturing remain major bottlenecks. In this Review, we survey current production strategies and therapeutic applications of synthetic circRNAs, and delineate engineering approaches that enhance molecular stability through nucleoside modification and sequence optimization, as well as strategies to improve translational efficiency, including internal ribosome entry site (IRES) and cap-mimicking elements, epitranscriptomic modifications, and rational sequence design. We further examine how these optimizations intersect with immunogenicity and process development, highlighting the critical quality attributes that govern circRNA product consistency and performance. Finally, we discuss emerging opportunities for algorithm-driven design and integrated engineering platforms, emphasizing their potential to accelerate the clinical translation of circRNA therapeutics.
