Pioneering Biomedical Applications with Intelligent Engineering

Intelligent engineered biomedicine fundamentally integrates dynamic environmental responsiveness with sophisticated data-driven architectures incorporating biochips, microfluidics, and robotic automation, collectively enabling next-generation personalized therapeutics. Contemporary advancements prioritize adaptive biomaterial systems that continuously detect, process, and react to complex biological signals through integrated technological frameworks spanning artificial intelligence (AI)-optimized chemical synthesis, molecular computation, and precision fluidic control. These interconnected platforms drive end-to-end biopharmaceutical innovation – from smart manufacturing and targeted delivery to closed-loop feedback mechanisms – positioning them as core enablers of precision medicine through enhanced therapeutic accuracy, minimized adverse effects, and patient-specific treatment paradigms. Implementation strategies bifurcate into top-down modifications of conventional biomedical platforms with programmable functionality and bottom-up engineering of intrinsically intelligent biomaterials through molecular-level design principles. To highlight the latest advancements in these fields, we have put together a Special Section titled “Intelligent Biomedical Engineering.” This collection includes 10 research articles, 1 perspective and 13 reviews from prominent scientists with their valuable insights.

Drug delivery emerges as a transformative cornerstone in intelligent biomedical engineering, where responsive nanomaterials synergize with AI-driven pharmacokinetic modeling and biofeedback-enabled nanodevices to enable dynamic, physiology-responsive therapeutics. These advanced systems utilize stimuli-activated carriers that intelligently modulate drug release in real-time based on biomarker fluctuations, achieving unprecedented spatiotemporal precision through engineered ligand-receptor targeting and biosensor-integrated automatic control. Tao Sun et al. develop a reactive oxygen species (ROS)-responsive heterodimer prodrug (VTO) combining oaldehyde dehydrogenase 2roxylin A (OA) and all-trans retinol (VA) linked via a thioketal bond to synergistically treat liver fibrosis (smtd.202402247). Encapsulated in biomimetic high-density lipoprotein, the co-delivery platform named PL-VTO nanoparticle leveraged natural liver targeting via scarvenger receptor type 1 binding. Upon reaching fibrotic liver, PL-VTO released OA and VA in response to elevated ROS levels, effectively scavenging ROS, deactivating hepatic stellate cells, and reducing collagen deposition. In vitro and in vivo studies demonstrated enhanced ROS clearance, targeted delivery, and fibrosis reversal with minimal toxicity, offering a promising multi-drug nanotherapeutic approach for liver fibrosis treatment. Hendrick W. de Haan and his coworkers investigate comb-shaped polymers for protein molecular sieving coatings (smtd.202500140). Simulations reveal three interaction regimes: no-, weak-, and strong-interactions between polymer chains, governed by steric hindrance, microenvironmental effects, and altered protein dynamics. Systematic parameter analysis identifies strategies to tune coating permeability and size selectivity, providing a universal framework for designing molecular sieving systems with controlled thresholds.

Hydrogels, as promising drug delivery platforms especially in the field of wound healing, were integrated into intelligent biomedicine by various groups. Yanli Zhao et al. introduce a photodynamic hydrogel activating aldehyde dehydrogenase 2 (ALDH2) to treat diabetic wounds by synergizing immune-vascular repair (smtd.202500391). ALDH2 deficiency in diabetic wounds exacerbates inflammation via neutrophil extracellular traps (NETs) and impairs angiogenesis. The hydrogel integrates ALDA-1 (ALDH2 activator) and chlorin e6, reducing NETs, polarizing macrophages to anti-inflammatory M2, and enhancing vascularization. In vivo tests show accelerated healing through dual modulation of inflammation and angiogenesis, offering a novel therapeutic strategy for chronic diabetic wounds. Chang Du and her coworkers develop an intelligent hydrogel platform (OGM) using gelatin modified with phenylboronic acid, oxidized dextran, and myricetin to accelerate diabetic wound healing (smtd.202401127). The hydrogel exhibits pH/ROS/glucose-responsive release of myricetin, effectively scavenging ROS, alleviating oxidative stress, and promoting angiogenesis via nuclear factor erythroid 2-related factor 2 pathway activation. In vitro and in vivo tests demonstrated enhanced cell proliferation, migration, and vascularization. This triple-responsive platform offers a promising strategy for diabetic wound care. Li Kong and his collaborators present a hydrogel-based immunochemotherapy system (smtd.202401425), to prevent post-surgical recurrence and metastasis in triple-negative breast cancer. The system combines doxorubicin-loaded nanoparticles (NPD) attached to platelets and interleukin-12 (IL-12) within a dopamine-modified alginate hydrogel. Upon activation in the tumor microenvironment, platelets release NPD-loaded microparticles that target residual/metastatic tumor cells, inducing immunogenic cell death. This strategy offers a promising localized therapy to enhance chemotherapeutic efficacy and immune activation post-surgery.

Exosomes are emerging as promising natural nanocarriers in drug delivery due to their innate biocompatibility, target-homing capabilities, and membrane stability. Current research focuses on engineering exosomal surfaces for enhanced tissue specificity, optimizing cargo loading techniques, and harnessing endogenous trafficking mechanisms. Seungpyo Hong et al. review researches in exosomes as theranostic tools in gastrointestinal cancers, highlighting their dual role as diagnostic biomarkers (miRNAs, lncRNAs, circRNAs, proteins) and engineered therapeutic carriers (smtd.202402058). It discusses advancements in exosome-based strategies for early detection, overcoming drug resistance, metastasis suppression, and immune modulation, addressing clinical challenges and future directions. Jiyong Liu et al. highlighted exosome-based vaccines as promising platforms for infectious diseases and cancer, leveraging their immunomodulatory properties, antigen presentation, and drug delivery capabilities (smtd.202402222). It discusses their biogenesis, components, preparation, and clinical applications, emphasizing personalized vaccine design while addressing challenges in standardization and clinical translation of exosome-based vaccines.

Advancements in other aspects of drug delivery systems including microneedles and oral drug delivery were highlighted by the contributors. Shutao Guo et al. discuss responsive microneedles for ocular drug delivery, addressing traditional limitations like low bioavailability (smtd.202402048). It categorizes responsive microneedles (pH, ROS, enzyme, glucose-triggered), highlighting their mechanisms and applications in treating diseases like glaucoma, diabetic retinopathy, and infections, emphasizing precision and reduced invasiveness. Wei Tao et al. summarize challenges in oral biologics delivery, including gastric acid, enzymatic degradation, and poor intestinal permeability (smtd.202401355). It highlights strategies like nanoparticle systems, ionic liquids, microneedles, and colon-targeted approaches to enhance bioavailability. Advances in delivery technologies may enable effective oral administration of biologics for chronic diseases.

Nanomedicine is revolutionizing intelligent biomedical engineering through the development of stimuli-responsive nanoplatforms that synergistically combine molecular targeting, biosensing capabilities, and controlled therapeutic delivery. Current research focuses on engineering smart materials with environmental sensitivity and precision targeting via ligand-receptor modifications, while integrating AI-driven nanoparticle design and adaptive biosensing systems. Notable advances include tumor-specific delivery platforms and blood-brain barrier penetrating systems, though challenges persist in predicting complex in vivo behaviors and establishing scalable manufacturing protocols. Emerging frontiers encompass DNA nanostructures for programmable drug carriers, organ-on-chip validation platforms, and computational pharmacokinetic models that simulate nanoparticle-body interactions. The field continues to evolve toward multifunctional theranostic systems capable of simultaneous diagnosis, real-time monitoring, and adaptive treatment modulation. Jinjin Shi et al. develop neutrophil-targeting biomimetic nanoparticles (MPB NPs) to treat atherosclerosis by inhibiting neutrophil extracellular trap (NET) formation (smtd.202402019). MPB NPs, composed of Prussian blue nanoparticles coated with bacterial membranes, specifically hitchhike on neutrophils via pathogen-associated molecular pattern recognition. By scavenging intracellularROS, MPB NPs suppress NET release induced by inflammatory stimuli. In atherosclerotic mouse models, MPB NPs remarkably reduced plaque area, stabilized plaques, and halted disease progression. This targeted approach demonstrates significant therapeutic potential for atherosclerosis and offers a platform for NET-related inflammatory diseases. Lin Mei et al. report a novel nanoparticle for treating idiopathic pulmonary fibrosis (IPF) by co-loading luteolin (Lut, an anti-fibrotic flavonoid) and hyaluronidase (HAase) into PEG-crosslinked nanoparticles (smtd.202400980). The Lut@HAase demonstrated enhanced lung accumulation via inhalation and deep tissue penetration through HAase-mediated hyaluronic acid degradation. In vitro, Lut@HAase suppressed TGF-β1-induced fibroblast activation (reducing α-SMA/FN expression), inflammatory cytokines (IL-6, IL-1β, TNF-α), and ROS in MRC5 cells. In bleomycin-induced IPF mice, inhaled Lut@HAase improved lung function (reduced resistance, increased compliance), decreased hydroxyproline content, attenuated fibrosis markers, and enhanced survival rates compared to free Lut or HAase, showcasing synergistic anti-fibrotic and anti-inflammatory effects. Si Li et al. develop chiral hydrogel microspheres (HMSs) incorporating L/D-Co₃O₄ nanoparticles to enhance lipase catalytic performance (smtd.202400918). By embedding lipase within L-Co₃O₄-HMSs, catalytic activity significantly increased compared to free lipase and was doubled than D-Co₃O₄-HMSs, attributed to the chiral microenvironment. The L-Co₃O₄-HMSs also demonstrated superior inhibition of 3T3-L1 fibroblast differentiation into adipocytes, highlighting their efficacy in lipid metabolism regulation. This work underscores the role of chirality in optimizing enzyme activity and offers a novel strategy for designing biomimetic catalytic systems with enhanced performance in industrial and biomedical applications. Jiao Yan review explorations in intelligent nanomaterials for osteoarthritis management, addressing its complex pathogenesis and current treatment limitations (smtd.202402263). It highlights nanomaterial innovations enabling targeted drug delivery, anti-inflammatory effects, and cartilage regeneration through engineered properties, emphasizing their clinical potential for personalized and effective osteoarthritis therapies. Hua Kuang et al. provide a review in nanomaterials (metal/metal oxide nanoparticles, liposomes, polymers) as vaccine adjuvants (smtd.202402059), highlighting their mechanisms: depot effect, NLRP3 inflammasome activation, receptor targeting, and cGAS-STING pathway activation. It discusses current clinical applications and challenges in optimizing safety, efficacy, and scalability for future use. Huan Meng et al. write a review discussing how nanomaterials induce pyroptosis, a lytic cell death releasing inflammatory cytokines, for therapeutic applications (smtd.202401290). Nanomaterials’ tunable properties (size, shape, charge) enable precise modulation of pyroptosis via inflammasome activation, enhancing targeted cancer and infection treatments while minimizing toxicity. Strategies include mRNA-based nanomedicine and controlled delivery systems to optimize efficacy. Another review paper in nanomedicine comes from Kui Luo et al. This paper reviews advancements in nanomedicine for enhancing non-small cell lung cancer (NSCLC) immunotherapy (smtd.202401783). It highlights strategies like immune checkpoint inhibitors, antibody-drug conjugates, cell engagers, adoptive cell therapy, and cancer vaccines. Nanomedicine improves drug targeting, bioavailability, and reduces toxicity while overcoming immune resistance. Innovations include nanoparticle-based delivery systems for PD-1/PD-L1 inhibitors, combination therapies, and TME modulation. Clinical trials show promising synergy with existing treatments, offering safer, more precise NSCLC therapies. Future directions focus on multifunctional nanoplatforms to optimize immunotherapy efficacy and patient outcomes. Let's see the last review paper in nanomedicine by Quanyin Hu. It reviews nanomedicine strategies for treating abdominal aortic aneurysms (AAA), addressing challenges like insufficient drug targeting and dynamic aortic environments (smtd.202402268). It highlights the role of inflammation, ECM degradation, and intraluminal thrombus in AAA progression, discussing nanoparticle-based therapies leveraging pathophysiological cues for localized drug delivery and improved clinical outcomes.

Biosensors are advancing intelligent biomedical engineering through innovations in wearable/implantable devices integrating nanomaterials, AI algorithms, and electro-bio interfaces. Current research emphasizes continuous biomarker monitoring (glucose, cytokines), multi-analyte detection, and on-site therapeutic systems. Nanoscale aptasensors and clustered regularly interspaced short palindromic repeats (CRISPR)-based detectors achieve unprecedented sensitivity. Challenges persist in long-term biocompatibility, signal drift correction, and interference minimization in complex biofluids. Emerging trends include self-powered biosensors using biopotential energy and synthetic biology-engineered living sensors for dynamic pathophysiological response tracking. Fengqin Li et al. report a DNA nanoflower (DNF)-powered CRISPR/Cas12a biosensing platform (DNF-CRISPR) for ultrasensitive protein detection (smtd.202402130). By integrating DNFs for upstream signal amplification and CRISPR/Cas12a for downstream trans-cleavage, the platform achieves a detection limit of sub-mg/L level, a broad dynamic range, and rapid results within 2 h. Validated using neutrophil gelatinase-associated lipocalin (NGAL) in kidney injury patients’ blood and urine, the platform demonstrated high accuracy, outperforming conventional ELISA. This approach enables precise, high-sensitivity protein marker detection, expanding CRISPR-based diagnostics to non-nucleic acid targets in clinical settings. Jiang Li et al. summarize recent advances in DNA-templated protein patterning, leveraging DNA nanotechnology for precise, programmable protein arrangements (smtd.202402249). It discusses covalent (e.g., crosslinkers, click chemistry) and non-covalent (e.g., biotin-streptavidin, aptamers) conjugation strategies. Applications span 1D to 3D nanostructures, dynamic patterns, and biomedicine (biosensing, nanovaccines, targeted therapies). DNA's addressability enables sub-10 nm precision, biocompatibility, and dynamic control. Challenges include conjugation efficiency, stability, and scalability. Future directions focus on integrating dynamic DNA systems for smart diagnostics/therapeutics and expanding functional complexity. Haisheng He et al. report a research work in PN-C18, a near-infrared-II (NIR-II) polarity-sensitive fluorescent probe with aggregation-caused quenching (ACQ) properties, to track in vivo lipolysis of lipid nanocarriers (smtd.202402249). PN-C18 overcomes interference from free probes and mixed micelles, enabling precise monitoring of lipid nanoparticle translocation and degradation. In vitro and in vivo experiments demonstrate its superior correlation with lipolysis progression and deep-tissue imaging capability. This approach advances understanding of lipid-based drug delivery systems’ in vivo fate, offering insights for optimizing oral drug formulations. Chiral biosensing is a research “hot-spot” in intelligent biosensors because chirality provided additional physical dimensions to biological systems. Ji-Young Kim et al. write a perspective highlighting advances in chirality quantification methods for optimizing nanophotonic biosensors (smtd.202500112). Chiral nanomaterials enhance sensitivity for detecting biomolecules via amplified chiroptical signals, but require deeper understanding of structural-optical chirality relationships. The perspective discusses near-field studies to probe chiral nano-bio interfaces and superchiral field effects. Key challenges include standardizing quantification metrics, improving nano-bio interactions, and unifying sensor signal analysis. Future directions focus on precise material design and standardized protocols to advance enantioselective biosensing for disease diagnostics and personalized medicine.

Finally, we are glad to see achievements in cutting-edge investigations of intelligent biomedicines in combinations of large-scale scientific facilities, smart soft robots, and deep-learning methodologies, largely expanding the scope of this special issue. Ying Zhu and her group review recent advances in synchrotron-based X-ray molecular probes for intelligent biomedicine (smtd.202401890). It highlights advanced imaging techniques and probes like antibody-coupled nanoparticles, genetically encoded tags, and targeted nanomaterials. Applications span cellular imaging, drug analysis, and disease diagnosis/therapy, with future trends focusing on AI-enhanced precision and personalized medicine. Zhengzhi Mu and his interdisciplinary teams gather research work in bioinspired soft robots (BSR) integrating biological motion mechanisms and rigid-flexible coupling systems for biomedical applications (smtd.202402264). Inspired by bending (e.g., Venus flytrap), twisting (e.g., octopus arms), and stretching (e.g., chameleon tongue) organisms, BSR leverage artificial muscle fibers, hydrogels, shape-memory alloys, and soft-rigid composites to achieve multi-degree-of-freedom deformations. Key design strategies mimic biological structures like soft tissues, rigid skeletons, and their synergistic interactions. Applications include in vivo tumor therapy, targeted drug delivery, and in vitro rehabilitative devices (e.g., bionic prostheses). Challenges remain in optimizing motion precision, environmental adaptability, and biocompatibility. Future directions emphasize advanced material integration and biomimetic control systems to enhance clinical translation and functionality in complex biomedical environments. Gang Bao et al. focus on predictions of off-target (OTS) risks of CRISPR/Cas editing (smtd.202500122). Deep learning methods like CRISPR-Net, R-CRISPR, and CRISPR-SGRU show promising OTS prediction capabilities when trained with validated off-target data. In this review, they evaluated six public datasets revealing integrating high-quality experimental OTS data enhances model robustness, particularly with imbalanced datasets. While no universal leader emerged, these models demonstrate improved precision and safety potential for clinical genome editing applications.

This special section of Small Methods proudly presents global breakthroughs in intelligent biomedicines, dedicated to fostering interdisciplinary collaboration between researchers and practitioners. We extend profound appreciation to all contributors that their research and review work exemplifies frontier innovations in this dynamic field. Gratitude is owed to the Small Methods editorial team, especially Dr. Xi Wen, for supplying us the chance to publish this special section.

The authors declare no conflict of interest.