Engineering Stimuli‐Responsive Materials for Precision Medicine

Abstract

Over the past decade, precision medicine has garnered increasing attention, making significant strides in discovering new therapeutic drugs and mechanisms, resulting in notable achievements in symptom alleviation, pain reduction, and extended survival rates. However, the limited target specificity of primary drugs and inter‐individual differences have often necessitated high‐dosage strategies, leading to challenges such as restricted deep tissue penetration rates and systemic side effects. Material science advancements present a promising avenue for these issues. By leveraging the distinct internal features of diseased regions and the application of specific external stimuli, responsive materials can be tailored to achieve targeted delivery, controllable release, and specific biochemical reactions. This review aims to highlight the latest advancements in stimuli‐responsive materials and their potential in precision medicine. Initially, we introduce disease‐related internal stimuli and capable external stimuli, elucidating the reaction principles of responsive functional groups. Subsequently, we provide a detailed analysis of representative pre‐clinical achievements of stimuli responsive materials across various clinical applications, including enhancements in the treatment of cancers, injury diseases, inflammatory diseases, infection diseases, and high‐throughput microfluidic biosensors. Finally, we discuss some clinical challenges, such as off‐target effects, long‐term impacts of nano‐materials, potential ethical concerns, and offer insights into future perspectives of stimuli‐responsive materials.

This review highlights the advancements in stimuli‐responsive materials within the realm of precision medicine. A comprehensive summary of the various stimuli and their corresponding response mechanisms is provided. Precision medicine applications, including disease therapies, imaging and diagnosis, are summarized. Furthermore, the review discusses the current challenges associated with stimuli‐responsive materials and offers insights into future research directions in precision medicine.

1. Introduction

Precision medicine is a medical discipline that integrates advances in basic scientific findings with the mechanisms of human diseases^{[ 1} , ² , ³ , ⁴ , ^{5 ]} Its aim is to provide novel treatment options for patients.^{[ 2} , ^{6 ]} In recent years, rapid developments in basic disciplines such as genomics,^{[ 7} , ^{8 ]} immunology,^{[ 9} , ^{10 ]} oncology,^{[ 11} , ^{12 ]} and pharmacology^{[ 13} , ^{14 ]} have revealed potential targets for clinical challenges, leading to the pioneering of new treatments,^{[ 15} , ^{16 ]} the construction of novel diagnostic methods,^{[ 17} , ^{18 ]} and successful prolongation of patient survival.^{[ 19} , ^{20 ]} However, both traditional treatments and novel options still face challenges and require further improvements. For example, while radiotherapy and immunotherapy can effectively eliminate tumor cells in cancer patients, they also inadvertently affect nearby normal cells, disrupt the normal immune responses, and cause toxic effects in multiple organs. These side effects often result in severe consequences and make it difficult for patients to the full course of treatment.^{[ 21} , ^{22 ]} In alignment with the fundamental purpose of precision medicine, researchers have begun developing various responsive biomaterials to integrate into clinical treatments, devoted to develop treatments that are better suited to individuals.^{[ 23} , ²⁴ , ²⁵ , ²⁶ , ^{27 ]} Prior to the advent of stimuli‐responsive biomaterials, researchers primarily relied on smart small molecules with specific structures to achieve targeting purposes.^{[ 28 ]} However, the complex discovery and synthesis processes associated with these small molecules limited their development.^{[ 29} , ^{30 ]} The emergence of stimuli‐responsive biomaterials has significantly improved this situation.^{[ 31} , ^{32 ]} By shifting the focus from overall structures to functional groups, stimuli‐responsive biomaterials offer enhanced structural versatility and controllability.^{[ 33} , ^{34 ]} Additionally, their larger size contributes to longer metabolic times,^{[ 35 ]} improved biocompatibility,^{[ 36 ]} and sustained release rates.^{[ 37 ]}

Recent advancements in medical research have unveiled distinct internal biochemical signatures of diseased tissues.^{[ 38} , ^{39 ]} For example, tumor tissues, with their heightened metabolic activity, were often found in a low pH environment with elevated intracellular glutathione (GSH) levels and exhibited abundant secretion of regulatory factors and exosomes.^{[ 40} , ^{41 ]} Similarly, in intestinal autoimmune diseases, diseased segments can secrete specific enzymes such as matrix metalloproteinases (MMP) and abundant esterases.^{[ 42} , ^{43 ]} Leveraging these characteristics, responsive drug delivery systems have been developed to precisely target diseased regions, reverse disease progression, and mitigate the side effects induced by excessive dosage.^{[ 44} , ^{45 ]} Moreover, researchers have discovered that adjunctive therapies utilizing external stimuli, such as photodynamic therapy,^{[ 46 ]} magnetodynamic therapy,^{[ 47 ]} and sonodynamic therapy,^{[ 48 ]} can significantly enhance treatment outcomes. Consequently, sensitizers for external stimuli, including near‐infrared sensitizers,^{[ 35} , ^{49 ]} ultrasound (US) sensitizers,^{[ 50 ]} magnetic field sensitizers,^{[ 51 ]} and electric field sensitizers,^{[ 52 ]} have been incorporated into responsive materials to offer a multidimensional treatment approach for patients. Apart from drug delivery systems in disease treatment, early diagnosis of existing diseases, monitoring of chronic diseases, and prediction of disease prognosis are critical aspects of precision medicine.^{[ 53} , ⁵⁴ , ^{55 ]} Thus, various biosensors based on responsive materials have been constructed for diverse applications, including the rapid and sensitive detection of pathogens in infectious diseases,^{[ 35} , ^{56 ]} tumor biomarkers in early cancers,^{[ 57 ]} glucose levels in diabetes patients,^{[ 58 ]} and even detection of drug residues.^{[ 59 ]}

In this review, we provide a comprehensive overview of recent advancements in stimuli‐responsive materials within the realm of precision medicine. Initially, we introduce the concept of stimuli and their interaction with responsive materials, elucidating the underlying principles governing the functionality of these agents in response to various stimuli. Subsequently, we meticulously examine the notable strides made by stimuli‐responsive materials in several key domain of precision medicine application, including cancer therapeutics, modalities for bone and wound healing, treatment of chronic inflammatory conditions, in vivo imaging techniques, and the development of innovative biosensors. Finally, we engage in an in‐depth discussion regarding the prospective opportunities and challenges encountered in the clinical deployment of stimuli‐responsive materials, offering insightful recommendations to navigate these challenges effectively in clinical settings (Figure 1 ).

Figure 1.

Overview of the significant achievements of engineering stimuli‐responsive materials in precision medicine.

2. Various Types of Stimuli‐Responsive Materials

2.1. pH‐Responsive Materials

The potential of hydrogen (pH) is a crucial biochemical indicator in the human system, with pH variations acting as a significant factor for materials and precision medicine.^{[ 60} , ⁶¹ , ^{62 ]} For instance, the internal pH of tumor tissue and infected wound surface typically ranged from 6.0 to 7.0 due to anaerobic respiration of cancer cells,^{[ 63 ]} bacteria, deviating significantly from the 7.2 to 7.4 range in the circulatory system.^{[ 64} , ⁶⁵ , ^{66 ]} This disparity underscored the potentials of designing acid‐responsive drug delivery systems to enhance specificity, improve treatment efficacy, and minimize side effects.^{[ 67} , ^{68 ]}

Synthesis strategies for acid‐responsive characteristics predominantly involve incorporating acid‐sensitive chemical bonds and “ionizable” chemical groups. In an acidic environment, acid‐sensitive bonds such as hydrazone, imine, ester, and amide bonds are vulnerable to proton attack, leading to structural breakdown and drug release. Similarly, “ionizable” chemical groups like carboxyl and amino groups, which maintain the stability of the drug delivery system, can undergo protonation and deprotonation in response to the presence or absence of protons, facilitating drug release.^{[ 69} , ⁷⁰ , ⁷¹ , ^{72 ]}

2.2. Redox‐Responsive Materials

Reduction‐oxidation (Redox) reactions, involving changes in a substrate's oxidation states, play a crucial role in maintaining the normal functioning of the human body.^{[ 73} , ^{74 ]} The balance between reactive oxygen species (ROS) and glutathione (GSH) is a prime example of redox equilibrium.^{[ 74 ]} ROS, a group of mitochondrial respiration byproducts, includes hydrogen peroxide (H₂O₂), superoxide anions (O^2•−), and hydroxyl radicals (•OH).^{[ 74} , ^{75 ]} GSH, a tripeptide compound, contains a readily oxidizable and dehydrogenatable thiol group, making it a major scavenger for O^2•− and H₂O₂. In cancerous and inflammatory diseases, the ROS and GSH levels in affected cells were significantly higher than in normal cells.^{[ 76 ]} Redox‐responsive structures, such as diselenide and disulfide bonds,^{[ 77 ]} ROS‐responsive structures, such as the ferrous ion (Fe²⁺) of Fe₃O_4, ^{[ 78} , ^{79 ]} and certain pre‐designed peptides and polymers, were employed to respond to high GSH or ROS environments, thereby fulfilling the objectives of precision medicine.^{[ 80} , ^{81 ]}

2.3. Photothermal‐Responsive Materials

Photodynamic therapy relied on the interaction between photons and photosensitizers to increase the surrounding temperature of photosensitizers and generate ROS in cell environments.^{[ 46 ]} Traditional organometallic photosensitizers typically consist of metal atoms like iridium, ruthenium, and rhodium, combined with chelated organic ligands.^{[ 82 ]} Recent advancements have seen a broader range of metals and organic ligands used in these photosensitizers, as well as the development of innovative organic and nanomaterial‐based alternatives.^{[ 83} , ^{84 ]} To cater to specific clinical requirements such as tumor targeting or prolonged tissue residency, various external structures like polypeptides, polymers, and metal‐organic frameworks (MOFs) have been incorporated to modify or encapsulate the metal centers of photosensitizers.^{[ 85} , ⁸⁶ , ^{87 ]}

2.4. US‐Responsive Materials

US has emerged as a prevalent clinical imaging technique due to its non‐invasive nature, cost‐effectiveness, and superior detection capabilities.^{[ 88 ]} Beyond imaging, US‐based sonodynamic materials also played a pivotal role in precision medicine applications, such as localized hyperthermia ablation,^{[ 89 ]} targeted drug delivery,^{[ 48 ]} and external stimulant.^{[ 90 ]} US responsiveness primarily occurred through two mechanisms: thermal and non‐thermal effects. The non‐thermal effect is directly dependent on acoustic energy, where the US waves induce cavitation in liquid flow, disrupt the structure of drug delivery materials, and trigger drug release.^{[ 91} , ^{92 ]} The thermal effect is exerted by the energy transition of acoustics. The propagation of US waves can significantly elevate the temperature of irradiated tissue, leading to high permeability in irradiated vessels and cells, or even cell death.^{[ 93} , ^{94 ]}

2.5. Magnetic‐Responsive Materials

Magnetic‐responsive materials have garnered increasing attention due to their extensive clinical application possibilities.^{[ 95 ]} Ferric oxide core‐shells, such as Fe₂O₃ and Fe₃O₄, are the most prevalent materials used to impart magnetic properties to nanoparticles.^{[ 96 ]} Leveraging these magnetic‐responsive characteristics, a multitude of clinical applications have been developed, including the enhancement of magnetic resonance imaging (MRI), magnetothermal‐based hyperthermia ablation, and targeted drug delivery guided by external magnetic fields.^{[ 97} , ^{98 ]}

2.6. Microfluidic Biosensors

The outbreak of acute and lethal infectious diseases, including COVID‐19, MERS, Dengue, Ebola, and Zika, has led to serious consequences.^{[ 99 ]} Traditional pathogen detection methods were hindered by intricate procedures, bulky machinery, and high costs.^{[ 100 ]} Consequently, researchers have begun focusing on the development of novel pathogen nucleic acid or antigen‐responsive materials to streamline processes and equipment, ultimately enhancing detection efficiency.^{[ 54} , ^{101 ]} Similarly, the demand for chronic disease monitoring, such as blood pressure, blood glucose, and uric acid, has also risen with the aging population. To address this similar issue, an increasing number of durable, cost‐effective, and minimally invasive, biomacromolecule or pressure responsive microfluidic biosensors have been developed to innovate existing technologies.^{[ 102} , ^{103 ]}

3. Applications of Stimuli‐Responsive Materials in in Precision Medicine

3.1. Immunotherapy

Immunotherapy, including immune checkpoint inhibitors such as programmed death 1 (PD‐1) inhibitors,^{[ 104 ]} programmed death‐ligand 1 (PD‐L1) activators,^{[ 105 ]} and cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) inhibitors,^{[ 106 ]} has significantly prolonged the survival of cancer patients.^{[ 107 ]} Despite its effectiveness, excessive immune checkpoint inhibition in normal immune cell can lead to severe autoimmune reactions, such as hypophysitis, thyroiditis, and hepatitis.^{[ 108} , ¹⁰⁹ , ^{110 ]} To improve targeting and minimize systemic side effects, Peng et al. developed a multi‐targeted immunotherapy system comprising a polypeptide, a photothermal dye, and docetaxel. The CF27 polypeptide possessed two ‐SH groups and a D‐peptide segment, providing a GSH‐responsive characteristic and blocking PD‐1/PD‐L1 recognition. The NIR dye IR820 served as a carrier for the chemotherapy drug docetaxel (DTX) and as a photothermal conversion agent for effective photothermal therapy. Both in vitro and in vivo experiments demonstrated that the exists of CF27 could effectively promote the tumor region accumulation of this GSH&NIR‐responsive delivery system and, showing a twofold increase in cancer cells and a 10.5fold increase in tumor tissues compared to DTX‐IR820 alone. Consequently, the GSH&NIR‐responsive immunotherapy system successfully reversed programmed cell death in effector T cells, significantly inhibiting tumor growth rate and volume. Moreover, NIR laser irradiation could quickly and locally raise the temperature of the tumor region, achieving combined photothermal therapy (Figure 2 ). This confirmed the versatility of GSH&NIR‐responsive immunotherapy system as a carrier for cancer combination therapies, responsive to the tumor microenvironment (TME) and photothermal therapy.^{[ 111 ]}

Figure 2.

Schematic illustration and achievements of GSH&NIR‐responsive immunotherapy. A) The structure of DTX‐IR820‐CF27. B) The in vitro targeted aggregation ability of DTX‐IR820‐CF27, C) The in vivo targeted aggregation ability between DTX‐IR820‐CF27. D) The photothermal effects of DTX‐IR820‐CF27. Reproduced with permission.^{[ 111 ]} Copyright 2019, John Wiley & Sons, Inc.

The Stimulator of interferon genes (STING) pathway is a key player in cancer immunotherapy, driving both the immunogenic cell death (ICD) of tumor cells and the antitumor response of immune cells.^{[ 112} , ^{113 ]} Capitalizing on this principle, Zhan et al. engineered a dual‐responsive nano‐potentiator capable of targeting both the TME and ultrasonic stimulation. This innovative nano‐potentiator featured chlorin e6 (Ce6), manganese dioxide (MnO₂), adenosine deaminase (ADA), and a ROS‐cleavable linker, functioning as a sonosensitizer, a TME‐responsive agent, and an immunotherapy drug, respectively. Upon exposure to US and the TME, Ce6 and MnO₂ generated ROS and Mn²⁺ to initiate a cascade of reactions. The generation of ROS activated the ROS‐cleavable linker, releasing ADA and triggering the STING pathways to recruit immune cells and amplify tumor‐killing effects. After 24 h nano‐potentiator injection into a deep tumor model, 10 min of US stimulation in the tumor region aggregated the fluorescent signals, markedly inhibiting the tumor growth rate and volume. Biochemical detection also revealed higher ROS and •OH levels, lower adenosine levels, and increased infiltration of immune cells such as dendritic cells and effector T cells into the tumor tissue. Under the combined action of sonodynamic therapy (SDT) and immunotherapy, tumor volume and weight were significantly inhibited over 16 days, achieving a satisfying therapeutic effect^{[ 114 ]} (Figure 3 ).

Figure 3.

Schematic illustration and achievements of dual‐cascade activatable NP_MCA. A) The synthetic route and mechanism of dual‐cascade activatable NP_MCA. B) The ROS generation effect of NP_MCA. C,D) The tumor elimination efficiency of NP_MCA. Reproduced with permission.^{[ 114 ]} Copyright 2023, John Wiley & Sons, Inc.

Researchers strive to balance enhancing therapeutic efficacy while minimizing adverse effects. Traditional high doses of drugs may effectively eradicate cancer cells, yet their broad targeting range often results in unintended destruction of healthy cells, leading to severe side effects and patient intolerance to treatment. Studies by Peng et al. and Zhan et al. have leveraged specific redox and TME cues, where these materials enabled the precise delivery of therapeutic agents such as immunotherapy drugs, chemotherapy drugs, imaging contrast agents, as well as NIR and US sensitizers to tumor tissues, effectively impeding tumor progression.^{[ 115} , ¹¹⁶ , ¹¹⁷ , ^{118 ]}

3.2. Radiotherapy

Despite the remarkable efficacy of targeted drugs and immunotherapy in treating various cancers, radiotherapy remains the primary treatment option for certain cancer types such as breast cancer,^{[ 119 ]} prostate cancer,^{[ 120 ]} small cell lung cancer,^{[ 121 ]} head and neck cancers.^{[ 122} , ^{123 ]} It also plays a crucial role in neoadjuvant treatment strategies.^{[ 124} , ^{125 ]} Su et al. developed a TME‐responsive radiation‐sensitizing effector system using MnO₂‐coated gold nanoparticles (AuNNPs@MnO₂) to enhance the radiotherapy efficacy. The TME‐responsive feature was achieved through a phosphate‐polystyrene‐modified bovine serum albumin (Ve@BSA) functional group, enabling the entry of GSH and the degradation of MnO₂, ultimately resulting in the aggregation of gold nanoparticles at the tumor site and allowing for deep tissue penetration of NIR II. In vivo xenograft liver cancer model experiments revealed that this TME‐responsive radiosensitizer system effectively accumulated at the tumor region, improving the imaging depth of NIR II. Importantly, compared to the PBS and negative control groups, the aggregation of gold nanoparticles significantly enhanced the therapeutic efficacy of radiotherapy at the same dose, leading to reduced tumor volume and prolonged survival of the model mice^{[ 126 ]} (Figure 4 ).

Figure 4.

Schematic illustration and achievements of TME‐responsive radiosensitizer system. A) The synthetic route and mechanism of AuNNPs@MnO₂. B) The targeted aggregation and NIR‐II imaging ability of AuNNPs@MnO₂ Ve@BSA C) The tumor elimination efficiency of AuNNPs@MnO₂ Ve@BSA. Reproduced with permission.^{[ 126 ]} Copyright 2023, Elsevier Ltd.

Small‐sized materials inherently possess superior tissue permeability and renal clearance, facilitating easy penetration into tumor tissue and rapid metabolism out of the body.^{[ 127} , ^{128 ]} Building on this concept, Zhang et al. developed a pH‐responsive small‐sized gold nanoparticle aimed at enhancing the tumor retention capacity of radiosensitizers. This system consisted of two types of negatively charged gold nanoparticles, designated as nanoparticle‐a and nanoparticle‐b. Under neutral pH conditions, such as in the bloodstream, the pH‐responsive small‐sized gold nanoparticle system maintained stability with an average size of 32 nm. However, within the acidic tumor microenvironment, the surface polypeptides of nanoparticle‐b underwent hydrolysis, converting nanoparticle‐b into a positively charged state. Through electrostatic interactions between the oppositely charged states, nanoparticle‐a and nanoparticle‐b aggregated to form a larger particle that accumulated within the tumor tissue. Radiosensitization experiments demonstrated that the pH‐responsive small‐sized gold nanoparticle system exhibited a significantly higher sensitizer enhancement ratio (SER) in the tumor region compared to individual nanoparticle‐a or nanoparticle‐b systems, resulting in fewer cells arrested at the S phase. Subsequent studies in xenograft cancer mice confirmed successful enrichment of the aggregated nanoparticles within the tumor tissue in an acidic environment. Notably, the presence of the aggregated gold nanoparticles enhanced the efficacy of a 4 Gy dose of radiotherapy compared to a 6 Gy dose without the gold nanoparticles, leading to a more pronounced tumor remission effect. Rapid plasma clearance of the small‐sized gold nanoparticles resulted in half of the particles being excreted through the kidneys within 1‐h post‐injection, with over 80% of the GNPs retained in the tumor region after 72 h^{[ 129 ]} (Figure 5 ).

Figure 5.

Schematic illustration and achievements of acid‐triggered GNPs. A) The aggregation mechanism of acid‐triggered GNPs. B) The compression of unaggregated and aggregated GNPs. C,D) The tumor elimination and aggregation efficiency of GNPs. Reproduced with permission.^{[ 129 ]} Copyright 2019, John Wiley & Sons, Inc.

In summary, radiotherapy operated by using emitted rays to indiscriminately eliminate cells within the irradiated area. While efforts were made to precisely delineate the irradiation field and protect surrounding non‐tumor tissues with lead shielding, the inherent side effects of long courses and high‐dose radiotherapy remained unavoidable. Due to their potent radiation enhancement effects, excellent biocompatibility, and unique optical properties, gold nanoparticles have emerged as popular radiation sensitizers.^{[ 130 ]} Su et al. and Zhang et al., respectively developed the redox‐responsive and pH‐responsive systems to precisely deliver the sensitizers to the tumor region.^{[ 126} , ^{129 ]} In recent years, more materials has been applied as sensitizers such as natural product sensitizers,^{[ 131 ]} inorganic nano sensitizers,^{[ 132 ]} and polymers sensitizers was constructed.^{[ 133 ]} Various multi‐responsive radiotherapy systems have been constructed, including hyaluronidase‐responsive,^{[ 134 ]} ROS‐responsive,^{[ 135 ]} and DNA damage response signaling pathway‐responsive sensitizer systems.^{[ 136} , ^{137 ]}

3.3. Imaging

Blood‐brain barrier (BBB) is the final barrier of central nervous systems, restricting the entry of harmful macromolecules such as bacteria, endotoxins, drugs, and contrast agents.^{[ 138} , ^{139 ]} To improve the passage rate of BBB, Villa et al. developed FluoroMags, a small, pH‐responsive, fluoromagnetic multimodal brain cancer imaging system. FluoroMags utilized small‐sized chrysotile carbon nanotubes (100–1000 nm) capable of traversing the BBB's cellular gaps (≈3000 nm). Two functional groups, anionic tetra(4‐sulfonatophenyl) porphyrin (H₂TPPS⁴⁻) and 11‐aminoundecanoate‐capped Fe₃O₄ (TAU−Fe₃O₄), were attached to the nanotubes’ surface, imparting acid‐responsiveness, fluorescence, and magnetism. In acidic tumor environments, the photophysical structure of H₂TPPS⁴⁻ underwent reversible modification, leading to fluorescence quenching, while the presence of TAU‐Fe₃O₄ significantly enhanced the magnetic resonance imaging (MRI) effect and allowed for H&E immunohistochemical staining. In vivo experiments confirmed that intravenously injected FluoroMags could successfully cross the BBB, primarily accumulate at the tumor site and surrounding vessels, and demonstrate multimodal imaging capabilities in MRI, immunofluorescence, and H&E immunohistochemistry. Early use of FluoroMags enabled long‐term tracking of tumor migration and recurrence. Villa et al. transplanted FluoroMags‐labeled glioblastoma multiforme (GBM) cells into nude mice, and the imaging characteristics of FluoroMags remained stable after 2 weeks and could be detected in metastases^{[ 140 ]} (Figure 6 ).

Figure 6.

Schematic illustration and achievements of FluoroMags. A) The synthetic route of FluoroMags. B) The compression of unaggregated and aggregated FluoroMags. C,D) The tumor imaging ability of FluoroMags in immunohistochemistry, immunofluorescence, and MRI. Reproduced with permission.^{[ 140 ]} Copyright 2018, John Wiley & Sons, Inc.

Epilepsy, a brain disorder, is characterized by focal abnormal discharges in the cerebral cortex.^{[ 141 ]} Over 15% of patients struggle with accurate lesion localization due to suboptimal MRI results.^{[ 142 ]} In response, Wang et al. introduced an electric‐field‐responsive MRI contrast agent composed mainly of a paramagnetic coat and a superparamagnetic core. The electric response and magnetic characteristics were primarily attributed to the ferrocene (Fc)‐contained core, which was suppressed by the paramagnetic Gd³⁺‐contained coat in stable situations. During abnormal discharge, the Fc core was ionized to Fc⁺, disrupting the spherical structure through intramolecular electrostatic repulsion and releasing superparamagnetic iron oxide to enhance MRI signals. Additionally, a low‐density lipoprotein receptor‐related protein 1 (LRP1) affinity peptide was incorporated to enhance the BBB passage rate and target brain cells. In epileptic mouse model experiments, this electric‐field‐responsive nanoprobe successfully crossed the BBB and tended to aggregate in LRP1‐rich areas. MRI results from chronic seizure mouse models showed that this intravenously administered electric‐field‐responsive nanoprobe had similar localization results to subdural electroencephalograms, with the signal strength in the discharge area enhanced by over 20% compared to normal areas.^{[ 143 ]} The use of ruthenium (Ru)‐based drugs is often limited by their narrow excitation and emission wavelengths, which can pose challenges for human tolerance. To overcome this, Li et al. developed a light‐responsive Ru metallacycle that emitted at wavelengths above 1000 nm. This advancement offered exceptional deep‐tissue penetration of ≈7 mm, and showed great promise for chemo‐phototherapy.^{[ 144 ]} Functional X ray contrast agents was also developed, respectively target to hypoxia environment,^{[ 145 ]} various pH environment,^{[ 146 ]} tumor microenvironment,^{[ 147 ]} and specific proteins,^{[ 148} , ^{149 ]} to enhance the imaging effect of different tissues in different organs.^{[ 150 ]}

3.4. Bone repair

Growth factor therapy is widely recognized as an effective approach for facilitating bone defect regeneration.^{[ 151 ]} However, current practices predominantly involved administering supraphysiological doses, potentially leading to side effects.^{[ 152 ]} Additionally, achieving synergistic effects with different types of growth factors concurrently has been challenging.^{[ 153 ]} To address this issue, Lv et al. developed a thermo‐responsive smart release hydrogel. The mental‐based chitosan/silk fibroin (CS)‐based hydrogel exhibited thermo‐responsive characteristics, enabling adaptive filling of defective bones. The rapid‐release growth factor was loaded with layered double hydroxide construction for sustained release, while slow‐release growth factor was embedded in CS hydrogels for burst release. In vitro studies revealed that the smart hydrogel could release the growth factors as needed, with over 80% of platelet‐derived growth factor‐BB (PDGF‐BB) released in 7 days and sustained release of Bone morphogenetic protein‐2 (BMP‐2) for 35 days, effectively enhancing migration activity and vessel formation capacity of human umbilical vein endothelial cells (HUVECs). In rabbit skull defect models, the thermo‐responsive hydrogel quickly filled the defect area within minutes. The dual growth factors smart release system significantly improved osteoblasts activity resulting in greater calcification and hard tissue was formation compared to no‐load or single growth factor‐loaded hydrogels, ultimately leading to satisfactory bone regeneration performance^{[ 154 ]} (Figure 7 ).

Figure 7.

Schematic illustration and achievements of thermo‐responsive smart release hydrogel. A) The synthetic route of MgFe‐layered double hydroxide (LDH) CS hydrogel. B) The injectable MgFe‐LDH CS hydrogel on different 3D patterns. C) The controllable release of PDGF‐BB and BMP‐2. D) The bone tissue regeneration promotion ability of MgFe‐LDH CS hydrogel. Reproduced with permission.^{[ 154 ]} Copyright 2018, John Wiley & Sons, Inc.

Bone defects larger than the critical size pose significant challenges for self‐repair,^{[ 155 ]} often necessitating amputation.^{[ 156 ]} Wang et al. developed a photoelectric‐responsive 3D biomimetic scaffold featuring hydroxyapatite (HA) nanocrystals that mimic the porous microstructure of natural spongy bone, creating a conducive environment for bone cell growth. Monocrystalline Si films embedded within the HA scaffold generated electrical stimulation through photoelectric reactions, effectively regulating cell activity and promoting bone repair. In vitro experiments demonstrated that the Si pillars array enhanced the osteogenic activities of mesenchymal stem cells (MSCs), promoting cell accumulation and adhesion with the formation of actin‐enriched filopodia‐like protrusions. Brief infrared (IR) illumination of the Si pillars triggered voltage signals in the nanoampere range, facilitating cell depolarization, redox reactions, and ROS generation essential for osteogenic. In a rat calvarium defect model, implantation of the 3D biomimetic scaffold combined with IR laser illumination every other day resulted in significant bone tissue regeneration within 8 weeks. The regenerated bone tissue exhibited increased bone mineral density, expanded tissue size, and nearly complete coverage of the defect site by the end of the treatment period^{[ 157 ]} (Figure 8 ).

Figure 8.

Schematic illustration and achievements of 3D biomimetic optoelectronic scaffold. A) The synthetic route and structure of 3D biomimetic optoelectronic scaffold. B) The degradation of 3D biomimetic optoelectronic scaffold. C) The setup for imaging the scaffold Ca²⁺ fluorescence. D) The optoelectronic depolarization process in cells. E) The biocompatibility of 3D biomimetic optoelectronic scaffold. Reproduced with permission.^{[ 157 ]} Copyright 2023, American Association for the Advancement of Science.

In recent studies, researchers have applied numerous materials including ceramics, glasses, metals, and polymers as the skeleton of 3D scaffold to achieve different characteristics such as high biocompatibility and high mechanically stable.^{[ 158} , ^{159 ]} Meanwhile, magnetic‐responsive scaffold also has been developed for bone repair therapy, as magnetic fields could stimulate osteoblasts proliferation and differentiation, regulate growth factor expressions, and accelerate bone healing.^{[ 160} , ¹⁶¹ , ^{162 ]} Liang et al. developed a biomimetic magnetic‐responsive scaffold by incorporating Fe₃O₄ magnetic nanoparticles into extracellular matrix (ECM)/regenerated silk fibroin (RSF) material. External magnetic field stimulation activated the scaffold, resulting in enhanced new bone volume, increased vascular network density in the defect region, and accelerated bone defect recovery in a critical size femur defect rat model. Transcriptome sequencing of bone marrow mesenchymal stem cells (BMSCs) revealed upregulation of calcium‐related pathways, suggesting that magnetic stimulation modulated Ca²⁺ signaling in osteogenesis, ultimately enhancing the bone repair process^{[ 162 ]} (Figure 9 ).

Figure 9.

Schematic illustration and achievements of magnetic‐responsive scaffold. A) The synthetic route and structure of magnetic‐responsive scaffold. B) The illustration of external static magnetic field. C) The micro‐CT manifestation of magnetic‐responsive scaffold in bone regeneration. Reproduced with permission.^{[ 162 ]} Copyright 2023, John Wiley & Sons, Inc.

Advancements in material science have led to a plethora of innovative options for bone repair therapy within the realm of precision medicine. Techniques such as injected hydrogels and 3D printed scaffolds offer tailored treatment solutions, addressing the specific needs of individual patients and serving as crucial therapeutic tools in the bone repair process.^{[ 159} , ¹⁶³ , ¹⁶⁴ , ¹⁶⁵ , ^{166 ]} Moreover, the integration of responsive materials expands treatment pathways and enables multi‐target therapy. By incorporating factors such as growth factors, photothermal, magnetic, and electrical stimulations, these approaches activate biological mechanisms synergistically, ultimately enhancing therapeutic efficacy.^{[ 167} , ^{168 ]}

3.5. Diabetic Ulcer Wound Healing

The complex microenvironment of diabetic ulcers, characterized by high glucose levels, bacterial infection, and low immune cells, presents a significant challenge for effective recovery.^{[ 169} , ^{170 ]} While wet dressing has shown promise in covering wounds and facilitating the healing process, while their limited duration and inability to provide controlled drug release hinder their efficacy.^{[ 27} , ¹⁷¹ , ^{172 ]} To further enhance wound healing, Zhu et al. developed a wound‐microenvironment responsive hydrogel dressing comprising photothermal responsive poly‐dopamine (PDA)‐modified gelatin and phenyl boronate acid modified hyaluronic acid (HA‐PBA). In a high glucose environment, the PBA group reacts with glucose to disrupt the hydrogel structure through the formation of boronate ester bonds. Furthermore, Copper (Cu) and metformin (Met) nanoparticles were integrated into the hydrogel to control drug release, reduce local glucose levels, eliminate reactive oxygen species (ROS), and regulate bacterial growth. Both in vivo and in vitro studies demonstrated that the hydrogel successfully enhanced cell activity, improved wound microenvironment, promoted cell angiogenesis, eliminated intracellular ROS, and reduced inflammatory factors. Histological analyses of diabetic SD rats revealed dense extracellular matrix (ECM) deposition and collagen accumulation in the wound area, indicating systemic wound recovery under the treatment of wound‐responsive hydrogel. This intelligent hydrogel was injectable and adaptable to various diabetic ulcer wound shapes. The treatment effects of wound‐responsive hydrogel were multi‐dimensional, with the active ingredients Met and Cu precisely targeting diabetes and its ulcers, effectively addressing high glucose and bacterial infections while promoting recovery. Importantly, its pH and glucose responsiveness prolonged the interval between dressing changes, which was crucial for diabetic ulcer wound recovery^{[ 173 ]} (Figure 10 ).

Figure 10.

Schematic illustration and achievements of Met@CuPDA hydrogel. A) The synthetic route and structure of Met@CuPDA hydrogel. B) The injectability, self‐healing ability of Met@CuPDA hydrogel. C) The bacteria inhibition efficiency of Met@CuPDA hydrogel. D) The wound repair ability of Met@CuPDA hydrogel. Reproduced with permission.^{[ 173 ]} Copyright 2023, Elsevier Ltd.

Exosomes were considered as promising agents for wound healing.^{[ 174} , ¹⁷⁵ , ^{176 ]} However, achieving suitable concentrations of exosomes in wounds via intravenous administration poses challenges, as high systemic concentration may lead to potential side effects.^{[ 177} , ^{178 ]} Jiang et al. developed a novel matrix metalloproteinases (MMPs)‐responsive polyethylene glycol (PEG) hydrogel for controllable release of exosomes. In MMP‐rich environments lie wounds, the hydrogel structure disintegrated, facilitating the release of exosomes as therapeutic agents. In vitro release studies demonstrated that over 80% of exosomes were released in an MMP‐2 environment after 20 days, while less than 10% were released in a non‐enzyme environment. In Streptozocin‐induced diabetic mice, the exosome‐loaded MMPs‐responsive hydrogel significantly accelerated skin regeneration rates in diabetic wounds. Cells covered with the hydrogel exhibited increased proliferation activity, fostering the formation of epithelialization tissue and collagen deposition in the skin defect region to promote the cutaneous appendages’ development.^{[ 179 ]} Similarly, Liu et al. developed a temperature‐responsive gelatin hydrogel for curcumin (CCM) delivery. With a phase transition temperature below 30 degrees, the hydrogel employed gelatin as a specific substrate for MMP9. This allowed patients to customize the hydrogel shape to fit their wound and enabled controlled CCM release in MMP‐rich environments.^{[ 180 ]} Yang et al. developed a MXene‐wrapped hydrogel with photo and magnetic responsiveness. Upon exposure to NIR and an alternating magnetic field, the hydrogel contracted and released silver nanoparticles to combat bacteria in diabetic ulcer wounds^{[ 181 ]} (Figure 11 ).

Figure 11.

Schematic illustration and achievements of MXene‐wrapped Fe₃O₄@SiO₂‐based hydrogel. A) The synthetic route and structure of MXene‐wrapped Fe₃O₄@SiO₂‐based hydrogel. B) The photothermal effect of MXene‐wrapped Fe₃O₄@SiO₂‐based hydrogel. C) The drug release process of MXene‐wrapped Fe₃O₄@SiO₂‐based hydrogel. D) The wound repair ability of MXene‐wrapped Fe₃O₄@SiO₂‐based hydrogel. Reproduced with permission.^{[ 181 ]} Copyright 2021, John Wiley & Sons, Inc.

While wet dressings offer numerous advantages including better biocompatibility, moisture retention, comfort, and patient compliance compared to traditional gauze bandages,^{[ 182} , ¹⁸³ , ^{184 ]} the complex microenvironment of diabetic ulcers poses challenges for effective treatment.^{[ 185 ]} Researchers have explored various responsive functional groups to enhance therapeutic targets and improve treatment outcomes.^{[ 27} , ^{186 ]} For instance, thermal‐responsive materials enabled custom shaping of wet dressings due to low phase‐transition temperatures, while wound microenvironment‐responsive materials like MMP‐responsive substrates enabled controlled release of therapeutic agents and extend the interval between dressing changes.^{[ 27} , ^{187 ]} Additionally, photothermal‐responsive,^{[ 188 ]} magnetic‐responsive,^{[ 189 ]} and electronic‐responsive materials^{[ 190 ]} introduced thermotherapy and electrical stimulation to enhance antibacterial effects and tissue regeneration capacity. With the aging population and growing awareness of diabetes complications, there is a growing focus on diabetic ulcer management, potentially expanding the market for these intelligent responsive wet dressings.

3.6. Chronic Inflammatory Disease

Osteoarthritis (OA) is a chronic degenerative disease characterized by reduced lubrication, inflammatory cell infiltration, and chronic disability.^{[ 191 ]} Current treatment strategies primarily involved oral nonsteroidal anti‐inflammatory drugs (NSAIDs) and steroid drugs for symptomatic relief.^{[ 192} , ¹⁹³ , ^{194 ]} To address the systemic side effects of NSAIDs and steroids and enhance treatment efficacy, Zhang et al. developed a pH‐responsive MOF hydrogel system targeting the acidic joint cavity to lubricate degenerative cartilage. This system also delivered multifunctional drugs, such as CCM and si‐HIF‐2α RNA, via MOF to improve treatment outcomes. In a mouse model of destabilized medial meniscus, the MOF‐CCM‐siRNA treatment effectively reversed knee‐joint damage, reduced osteophyte formation, and improved lubrication. Histological analyses confirmed greater morphological integrity, fewer severe lesions, and reduced surface denudation in the treatment group, highlighting the therapeutic potential of this approach.^{[ 195 ]} Meanwhile, Shi et al. developed a NIR‐responsive Molybdenum (Mo)‐based polyoxometalate (POM) clusters for photothermal therapy and ROS clearance in the knee joint. Shi et al. used the sodium iodoacetate (MIA) model as the OA model. The NIR‐POM group demonstrated a superior therapeutic effect, with lower arthritis scores, improved kinematic scores, and more intact cartilage shapes. This outcome may be attributed to the anti‐inflammatory effects of ROS scavenging, leading to reduced levels of ROS and various inflammatory factors such as IL‐6 and extracellular MMP13.^{[ 196 ]} Similar, Xia et al. constructed a ROS & collagenases dual‐responsive hydrogel to adapt to the OA microenvironment. Then, they packaged a natural sirtuins 3 (SIRT3) agonist dihydromyricetin (DMY) into the hydrogel to activate the SIRT3 pathway and maintain mitochondrial apoptosis and Mitophagy stability^{[ 197 ]} (Figure 12 ).

Figure 12.

Schematic illustration and achievements of DMY‐HGP. A) The synthetic route and structure DMY‐HGP. B) The fluorescent radiant efficiency of DMY‐HGP. C) The treatment effect of DMY‐HGP. Reproduced with permission.^{[ 197 ]} Copyright 2023, John Wiley & Sons, Inc.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease prevalent in women, characterized by chronic inflammatory cell infiltration across multiple organs, leading to various systemic syndromes.^{[ 198 ]} Recent research has indicated that selective elimination of nitric oxide (NO) could effectively treat arthritis.^{[ 199 ]} Kim developed an injectable NO‐responsive hydrogel capable of in situ NO elimination, lubricating articular cartilage, and facilitating controlled release of anti‐inflammatory drugs. This hydrogel featured a NO‐responsive functional group via a dialkyne‐functionalized NO‐cleavable cross‐linker tagged to the HA skeleton, enabling NO consumption, joint lubrication, and subsequent drug release^{[ 200 ]} (Figure 13 ).

Figure 13.

Schematic illustration and achievements of NO‐responsive HA hydrogel. A) The synthetic route and structure NO‐responsive HA hydrogel. B) The NO responsive mechanism of HA hydrogel. C,D) The treatment effect of NO‐responsive HA hydrogel. Reproduced with permission.^{[ 200 ]} Copyright 2021, John Wiley & Sons, Inc.

Ulcerative colitis (UC), a chronic inflammatory bowel disease affecting various parts of the gastrointestinal tract, especially the lower colon and rectum,^{[ 201 ]} often faced challenges with conventional drug treatments due to premature absorption in the upper colon, resulting in elevated systemic drug concentrations.^{[ 202 ]} In UC, an imbalance of esterases, such as phosphodiesterases, and specific colonic microflora are characteristic features. According to these characteristics, Chen et al. developed an esterase‐responsive chitosan‐modified liposome delivery system. This system achieved controlled release of dexamethasone at the diseased region by utilizing esterases and colonic microflora enzymes to cleave the lipid bonds and chitosan shells of the liposomes, respectively.^{[ 203 ]}

In summary, the treatment of chronic inflammatory diseases has long been challenged by complex pathogenic mechanisms, significant individual variations, and the absence of an effective drug delivery systems. Patients often endure severe systemic side effects of immunosuppressive medications, while researchers seek innovative treatment strategies. Recent advancements in novel stimuli‐responsive materials offer a promising avenue. These materials are engineered to target the unique features of chronic inflammatory diseases, such as the acidic pH environments from immune cell infiltration, pathologically secreted enzymes, disturbances in redox reactions, and alterations in tissue composition. By releasing drugs precisely at affected regions as needed, stimuli‐responsive materials have the potential to minimize dosages, reduce side effects, enhance patient compliance, improve treatment efficacy, and ultimately extend survival rates.

3.7. Anti‐Bacteria

The escalation of bacterial resistance is rendering numerous antibiotics ineffective against emerging drug‐resistant bacteria, posing a substantial global public health threat.^{[ 204} , ^{205 ]} Photodynamic therapy emerged as a promising antibiotic‐free antimicrobial therapy. Over recent decades, rapid advancements in photosensitizers technology have led to the creation of more targeted and versatile photodynamic systems, aimed at enhancing treatment outcomes.^{[ 86} , ²⁰⁶ , ^{207 ]} Titanium dioxide (TiO₂) biomaterials find extensive clinical utility due to their high biocompatibility and antibacterial properties.^{[ 208 ]} However, TiO2's wide bandgap limited its activation to UV light, unsuitable for in vivo use. To address this challenge, Cheng et al. introduced a PDA‐ligand as a photon catcher to absorb NIR light and transfer energy to a TiO2 composite through a ligand‐to‐metal charge transfer process. In vitro experiments targeting Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), biofilms representatives of Gram‐negative and Gram‐positive bacteria, demonstrated TiO₂‐PDA's antibacterial efficacy within 5 min of NIR irradiation, reducing biofilm CFU counts in both strains. Leveraging PDA's ultrasonic response enhanced TiO2‐PDA's antibacterial efficacy through combined NIR and US exposure. Subsequent in vivo experiments in a mouse cutaneous wound model demonstrated that NIR‐US effectively controlled E. coli infections, reducing colony numbers within the wound and promoting healing process. Histological analysis of the stained wound photos revealed reduced neutrophil infiltration, increased collagen deposition, and enhanced extracellular matrix formation, thereby accelerating wound healing^{[ 209 ]} (Figure 14 ).

Figure 14.

Schematic illustration and achievements of TiO₂‐PDA system. A) The synthetic route and structure TiO₂‐PDA system. B) The in vitro bacteria inhibition effect of TiO₂‐PDA‐NIR‐US system C) The in vivo photothermal effect of TiO₂‐PDA system. D) The wound repair ability of TiO2‐PDA‐NIR‐US system. Reproduced with permission.^{[ 209 ]} Copyright 2022, John Wiley & Sons, Inc.

This innovative organic‐inorganic composite structure overcame traditional photosensitizers limitations, broadening the range of antibacterial materials interacting with NIR light and advancing photodynamic therapy.^{[ 210 ]} In contrast to materials focusing solely on biocompatibility and antibacterial activity, Zhong et al. developed a self‐adaptive dressing to precisely address wound healing phases and promote overall recovery. This dressing comprised an acid‐responsive cellulose sulfate (CS) outer layer and an antibacterial quaternary ammonium salt (QAS) inner layer. During the initial infection phase, characterized by a slightly acidic wound microenvironment, the outer layer detached to expose the inner layer. As bacteria were eradicated and tissue regeneration progressed, the wound pH neutralized, causing outer layer to re‐cover the inner layer, minimizing potential toxic reactions. In rat models infected with S. aureus, the double layer hydrogel demonstrated comparable antibacterial efficacy to a simple layer hydrogel, yet exhibited superior biocompatibility, significantly enhancing infected wound recovery, evident by larger skin recovery area by day 14^{[ 211 ]} (Figure 15 ).

Figure 15.

Schematic illustration and achievements of QAS‐Hap hydrogel. A) The synthetic route and structure QAS‐Hap hydrogel. B,C) The pH‐responsive characteristic of QAS‐Hap hydrogel D) The in vitro bacteria inhibition effect of QAS‐Hap hydrogel. E) The wound repair ability of QAS‐Hap hydrogel. Reproduced with permission.^{[ 211 ]} Copyright 2022, John Wiley & Sons, Inc.

Various stimuli‐responsive nanoplatforms have been developed and exhibited great potential in combating bacterial resistance, capitalizing on both endogenous features and exogenous conditions.^{[ 212 ]} Bacterial infections exhibited diverse endogenous features, including acidic pH environment, specific enzyme secretions, local endotoxin accumulation, and bacterial specific surface proteins, which could active stimuli‐responsive nanoplatforms, modify material nanostructure, and enable controllable release of antibacterial agents.^{[ 213} , ²¹⁴ , ^{215 ]} Furthermore, due to the excellent antibacterial effects of local hyperthermia, ultrasound, and oxidizing agent, novel photosensitizer, sonosensitizer, and magnetic sensitizer were integrated into nanoplatforms to fulfill the multi‐targets therapy.

3.8. Microfluidic Biosensors

Diabetes, a prevalent endocrine diseases globally, necessitated over 500 million daily blood glucose tests worldwide.^{[ 99 ]} However, the invasive fingertip blood collection methods and costly enzymatic blood glucose machines impede patients' adherence to regular blood glucose monitoring.^{[ 99} , ^{216 ]} Hsu et al. developed a microneedle‐based glucose‐biosensing system for syringe‐free blood glucose monitoring. The system comprised one hundred glucose oxidase (GOx)‐MnO₂ conjugated hydrogel‐based microneedles that penetrate the dermis layer to collect skin interstitial fluid for glucose level analysis. Upon contact with glucose, GOx within the microneedles reacts to produce gluconic acid and H₂O₂. Subsequently, H₂O₂ facilitated the interaction between 3,3′,5,5′‐tetramethylbenzidine (TMB) and MnO₂, resulting in a color change from colorless to blue on the microneedles. In vitro studies demonstrated the high specificity of GOx for glucose and the stability of glucose level analysis across a pH range of 3 to 11. Moreover, in vivo experiments showed that the microneedles accurately distinguished between sub‐hyperglycemia (≥200 mg dl⁻¹) and hyperglycemia (≥300 mg dl⁻¹) in diabetic rats compared to healthy rats (≤120 mg dl⁻¹), with the microneedles displaying cyan and blue colors, respectively^{[ 58 ]} (Figure 16 ).

Figure 16.

Schematic illustration and achievements of On‐skin glucose‐biosensing microneedle array. A) The synthetic route, structure, and mechanism of glucose‐biosensing microneedle. B) The reaction of GOx‐MnO₂@GO with glucose. C,D) The reaction of microneedle array with different glucose concentrations in fluorescent field and bright field. Reproduced with permerssion.^{[ 58 ]} Copyright 2020, Elsevier Ltd.

Yan et al. engineered a glucoamylase‐based “sweet hydrogel” capable of detecting multiple non‐glucose targets. This hydrogel incorporated two DNA sequences onto polyacrylamide polymers to entrap glucoamylase, forming a stable complex with amylose. Upon binding of detection targets such as cocaine to the hydrogel, the two DNA sequences facilitated adapter lysis, breaking down the hydrogel and releasing glucoamylase. Consequently, glucoamylase catalyzed amylose to produce glucose, quantified using a glucometer. Following optimization, this sweet hydrogel successfully detected cocaine metabolites benzoylecgonine and ecgonine methyl ester, with a detection limit of 1.6 µM, comparable to commercial cocaine test kits.^{[ 59 ]}

As research on exosomal microRNA continues to advance, specific miRNAs have been identified as potential tumor markers for monitoring tumor development. However, complexities in collecting miRNAs from exosomes have impeded the clinical application of these biomarkers.^{[ 216} , ²¹⁷ , ²¹⁸ , ^{219 ]} Therefore, Rokshana et al. implemented a nanoparticle‐based approach to isolate exosomes and developed a photothermal responsive digital PCR system for high‐resolution miRNA detection. Initially, biotin functionalized SiO₂ nanoparticles captured exosomes non‐specifically, reducing the collection process to 1 h. Subsequently, a NIR‐responsive SiO₂ nanoparticle system facilitated PCR amplification of tumor biomarkers without the need for a traditional PCR thermal‐cycler. By incorporating MoS₂ nanosheets onto the nanoparticles' surface to confer photothermal properties, a photothermal responsive digital PCR system was created. This system, accurately detected significant differences in miRNA‐200b‐3p, miRNA‐21‐5p, and miRNA‐22‐3p levels within two distinct liver cancer cell lines^{[ 57 ]} (Figure 17 ). Similar, Kim et al. developed a primer‐immobilized networks based photothermal microparticles system. The heating rate and cooling rate of photothermal microparticles system could over 20 °C per second, which could complete a 40 cycles PCR program in 5 min. Relying on this photothermal microparticles system, E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii were discriminated and reached 100 copies µL⁻¹ detection limitation^{[ 220 ]} (Figure 18 ).

Figure 17.

Schematic illustration and achievements of photothermal responsive digital PCR system. A) The synthetic route and structure of photothermal responsive MoS2‐SiO2 nanoparticles. B) The photothermal temperature variation of digital PCR system. C) The Arduino controlled NIR photothermal digital PCR instrument. D) The amplification efficiency of photothermal responsive digital PCR system. Reproduced with permission.^{[ 57 ]} Copyright 2022, John Wiley & Sons, Inc.

Figure 18.

Schematic illustration and achievements of photothermal microparticles qPCR system. A) The synthetic route and reaction principle of photothermal microparticles qPCR system. B) The amplification curve of different pathogen concentrations. C) The serial snapshots of photothermal microparticles. D) The multiplex bacterial discrimination. Reproduced with permission.^{[ 220 ]} Copyright 2022, American Chemical Society.

With the prevalence of COVID‐19^{[ 221} , ²²² , ^{223 ]} and other respiratory infections such as mycoplasma pneumonia,^{[ 224 ]} tuberculosis,^{[ 225 ]} influenza,^{[ 226 ]} and MERS,^{[ 227 ]} conventional detection methods like PCR and antibody assay face limitations in time, power source, and detection specificity.^{[ 228} , ^{229 ]} Na et al. introduced a pathogen response hydrogel coupled microfluidic device to enhance the detection performance. Within this device, agarose gel beads incorporated primers and probes for rolling circle amplification (RCA). As amplification progressed, elongated dumbbell‐shaped long DNAs activated the DNA‐responsive hydrogel, causing it to expand over 10 000 times. This innovative microfluidic device successfully detected Dengue, MERS, Ebola, and Zika within 15 min, with a detection limit 10–100 times higher than previous methods. Notably, the use of the DNA‐responsive hydrogel enabled direct visual detection of results, reducing costs and broadening applicability^{[ 56 ]} (Figure 19 ).

Figure 19.

Schematic illustration and achievements of pathogen responsive hydrogel. A) The synthetic route and reaction principle of pathogen responsive hydrogel. B) The fluorescence effect of pathogen detection microbeads. C) The operation illustration of pathogen responsive hydrogel. D) The pathogen detection results of pathogen responsive hydrogel. E) The wound repair ability of QAS‐Hap hydrogel. Reproduced with permission.^{[ 56 ]} Copyright 2022, John Wiley & Sons, Inc.

In conclusion, the glucoamylase‐based microneedle and hydrogel systems offered a cost‐effective, straightforward, and rapid solution for detecting multiple targets. The microneedle array served as an innovative sample collection device, capable of painlessly extracting blood and interstitial fluid samples from the skin's dermis layer due to its fine diameter. Beyond glucose, the microneedle‐based biosensors have been successfully utilized to quantitatively measure alcohol, nitric oxide, ascorbic acid, bacteria, proteins, antibodies, and the like.^{[ 230 ]} The development of the “sweet hydrogel” concept present new possibilities for precision medicine. Unlike lateral flow test methods that require linking antibodies on a flow tape, limiting detection to one target substance per tape, the DNA strains in the adapter system can be easily customized based on specific testing requirements, enabling efficient multi‐target testing capabilities. Leveraging the progress in microfluidic devices and responsive materials, the healthcare sector has witnessed rapid advancements in smart biosensors, including wearable biosensors,^{[ 231 ]} paper‐based biosensors,^{[ 232 ]} smartphone‐based biosensors,^{[ 233 ]} and rapid pathogen detection biosensors.^{[ 234 ]} These innovations have been tailored to meet the demands of precision medicine, offering promising prospects for further growth in this domain.

4. Challenges of the Stimuli‐Responsive Materials in Precision Medicine

4.1. Off‐Target Effect

Off‐target effects pose a significant concern and an inevitable challenge associated with targeted delivery systems. In pre‐clinical animal model research, stimuli‐responsive materials have demonstrated remarkable targeted delivery effects, with fluorophores precisely accumulating in diseased regions. However, substantial differences existed among patients, including variations in intercellular space size, organ permeability of substances, and complex stress states, not to mention discrepancies between animal models and human physiology. Therefore, while pre‐clinical results were promising, clinical trials were imperative to validate the feasibility of stimuli‐responsive materials within the human body, systematically analyzed targeting effects, and longitudinally collected follow‐up data. In recent years, the rapid advancement of artificial intelligence has facilitated the application of numerous algorithms to predict the binding rates of macromolecular substances. This approach effectively reduced early trial and error costs and provided new insights for future designs of stimuli‐responsive materials.

4.2. Metabolic Accumulation Issue

The stimuli‐responsive materials comprised macromolecular substances, which typically cannot be directly metabolized by the circulatory system and instead require degradation by the metabolic system into smaller‐sized materials.^{[ 235 ]} While researchers have primarily focused on the fluorescence‐labelled materials, with most fluorescent signals aggregating at diseased regions, the metabolites of macromolecular materials have not received adequate attention. Therefore, further research is warranted to delve into the deeper evidence regarding the long‐term toxicity, biological activity, immunogenicity, and organ accumulation of these metabolites. This comprehensive investigation is essential to verify the safety profile of macromolecular materials and ensure their suitability for biomedical applications.

4.3. Ethical Issue

The advancement of stimuli‐responsive materials in medicine has propelled significant progress, but also raised ethical considerations that demand attention. Equitable access to these technologies is crucial; while these emerging therapies hold promise, there's a risk of widening the gap between medical resources available to different socioeconomic groups. Overemphasis on high‐cost therapies may impede the development of more affordable alternatives, exacerbating disparities in healthcare accessibility. Concerns about dual use are also relevant; while stimuli can control drug release in targeted delivery systems, they could also be exploited for malicious purposes, such as bioterrorism. Therefore, rigorous review and scrutiny of information related to stimuli‐responsive materials are essential before dissemination. Additionally, long‐term follow‐up and monitoring of patients undergoing targeted delivery system therapies are indispensable for assessing treatment efficacy, safety, and the emergence of potential late‐onset effects, ensuring patient welfare and addressing any unforeseen consequences of therapy.

4.4. Multi‐purposes Balance

Understanding the interactions among various components and their behavior in biological environments are essential for achieving synergistic effects or multiple response modalities. Each unit should be tailored to fulfill its specific role while collaborating with others. For instance, therapeutic agents should be optimized for their delivery methods, ensuring stability while maximizing local efficacy and minimizing systemic side effects. Likewise, imaging agents must be precisely calibrated for sensitivity and specificity to accurately identify target tissues or disease states. Furthermore, grasping the mechanisms driving the stimuli responsiveness of these materials is crucial, which necessitates careful consideration of properties like size, surface charge, and chemical composition. A comprehensive strategy that includes multi‐faceted optimization and iterative testing can significantly improve outcomes, requiring customized design and optimization based on specific needs.

5. Conclusion and Perspectives

Translational research on stimuli‐responsive materials for precision medicine is rapidly progressing, with researchers developing a variety of response systems tailored to diverse stimuli across various diseases. These stimuli include pH levels, unbalanced reduction‐oxidation reactions, microenvironments, and specific proteins, enabling precise drug delivery systems and yielding excellent treatment outcomes. Moreover, the integration of external stimuli such as light, US, magnetic fields, and electric fields with drug delivery systems has enabled multidimensional dynamic therapies. Additionally, the development of responsive materials based multimodal imaging agents and wearable flexible biosensors plays a crucial role in early diagnosis, continuous monitoring, and prognosis prediction. While stimuli‐responsive materials have demonstrated remarkable efficacy in pre‐clinical settings, their translation into clinical applications necessitated intensified efforts. Currently, clinical trials of stimuli‐responsive drug delivery systems are scarce. Challenges associated with stimuli‐responsive materials primarily revolve around accurately quantifying off‐target effects, addressing the long‐term multi‐organ toxicity necessitating prolonged follow‐up, and navigating ethical considerations that demand rigorous scrutiny. Therefore, we advocate for researchers to conduct prospective clinical trials, systematically assess potential side‐effects, and objectively compare the efficacy enhancements offered by stimuli‐responsive materials.

In summary, stimuli‐responsive materials have undergone substantial advancements in drug delivery systems, multimodal imaging agents, and multifunction biosensors, underscoring their unique advantages. Nonetheless, the long‐term safety implications of in vivo stimuli‐responsive material therapy warrant further investigation, thereby paving the way for a promising future in biomedical applications.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

R.Z. and C.Y. contributed equally to this work and are listed as co‐first authors. R.X.Z. and Y.C. analyzed the literature, prepared the figures and tables, and drafted the manuscript. D.Y. and M.S.C. edited the manuscript. X.Y.H., F.F.Y., and L.X.Z. conceived the study, supervised the work, and revised the manuscript. All authors have read and approved the final manuscript.

Biographies

Ruixuan Zheng is a Ph.D. student of Wenzhou Medical University. His current research interests lie in CRISPR‐Cas9 based rapid clinical pathogen detection, CRISPR‐Cas9 based translational medicine research and interdisciplinary application of responsive biomaterials.

Lexiang Zhang received his Ph.D. in chemical engineering in 2016 from Tianjin University, and then worked as a postdoctoral researcher in David Weitz lab at Harvard University. He joined the Wenzhou Institute, University of Chinese Academy of Sciences as Associate Researcher in 2020. His current research interests include droplet microfluidics, single cell sequencing, responsive biomaterials, and their applications in biomolecular analysis.

Fangfu Ye received his Ph.D. in physics in 2007 from the University of Pennsylvania and later he worked as a postdoctoral research associate at the Liquid Crystal Institute of Kent State University, the Department of Physics of University of Illinois at Urbana‐Champaign, and the School of Physics of Georgia Institute of Technology, successively. He joined the Institute of Physics of Chinese Academy of Sciences in 2013. His current research interests lie in interdisciplinary areas between physics and biology, including cell mechanics, cell migration, extracellular matrix‐cell interaction, development of organoids, active matter, etc.

Xiaoying Huang received her Ph.D. in clinical medicine of integrated traditional Chinese and western medicine in 2011 from the Zhejiang Chinese Medical University and later she worked at the First Affiliated Hospital of Wenzhou Medical University. Her current research interests lie in the innovative drug therapy and mechanism exploration of lung diseases, targeted drug delivery systems, rapid clinical pathogen detection, etc.

Zheng R., Yu C., Yao D., Cai M., Zhang L., Ye F., Huang X., Engineering Stimuli‐Responsive Materials for Precision Medicine. Small 2024, 21, 2406439. 10.1002/smll.202406439