Silica-based scaffolds are promising in Tissue Engineering by enabling personalized scaffolds, boosting exceptional bioactivity and osteogenic characteristics. Moreover, silica materials are highly tunable, allowing for controlled drug release to enhance tissue regeneration. In this study, we developed a 3D printable silica material with controlled mesoporosity, achieved through the sol-gel reaction of tetraethyl orthosilicate (TEOS) at mild temperatures with the addition of different calcium concentrations. The resultant silica inks exhibited high printability and shape fidelity, while maintaining bioactivity and biocompatibility. Notably, the increased mesopore size enhanced the incorporation and release of large molecules, using cytochrome C as a drug model. Due to the varying surface charge of silica depending on the pH, a pH-dependent control release was obtained between pH 2.5 and 7.5, with maximum release in acidic conditions. Therefore, silica with controlled mesoporosity could be 3D printed, acting as a pH stimuli responsive platform with therapeutic potential.

Drug-resistant infectious diseases pose a substantial challenge and threat to medical regimens. While adaptive laboratory evolution provides foresight for encountering such situations, it has inherent limitations. Novel drug delivery systems (DDSs) have garnered attention for overcoming these hurdles. Multi-stimuli responsive DDSs are particularly effective due to their reduced background leakage and targeted drug delivery to specific host sites for pathogen elimination. Bacterial infections create an acidic state in the microenvironment (pH: 5.0-5.5), which differs from normal physiological conditions (pH: 7.4). Infected areas are characterized by the overexpression of hyaluronidase, gelatinase, phospholipase, and other virulence factors. Consequently, several effective stimuli-responsive DDSs have been developed to target bacterial pathogens. Additionally, biofilms, structured communities of bacteria encased in a self-produced polymeric matrix, pose a significant challenge by conferring resistance to conventional antimicrobial treatments. Recent advancements in nano-drug delivery systems (nDDSs) show promise in enhancing antimicrobial efficacy by improving drug absorption and targeting within the biofilm matrix. nDDSs can deliver antimicrobials directly to the biofilm, facilitating more effective eradication of these resilient bacterial communities. Herein, this review examines challenges in DDS development, focusing on enhancing antibacterial activity and eradicating biofilms without adverse effects. Furthermore, advances in immune system modulation and photothermal therapy are discussed as future directions for the treatment of bacterial diseases.

OBJECTIVE: Oral diseases, such as dental caries, periodontitis, and oral cancers, are highly prevalent worldwide. Many oral diseases are typically associated with bacterial infections or the proliferation of malignant cells, and they are usually located superficially.
METHODS: Articles were retrieved from PubMed/Medline, Web of Science. All studies focusing on stimuli-responsive materials in oral diseases were included and carefully evaluated.
RESULTS: Stimulus-responsive materials are innovative materials that selectively undergo structural changes and trigger drug release based on shifts at the molecular level, such as changes in pH, electric field, magnetic field, or light in the surrounding environment. These changes lead to alterations in the properties of the materials at the macro- or microscopic level. Consequently, stimuli-responsive materials are particularly suitable for treating superficial site diseases and have found extensive applications in antibacterial and anticancer therapies. These characteristics make them convenient and effective for addressing oral diseases.
CONCLUSIONS: This review aimed to summarize the classification, mechanism of action, and application of stimuli-responsive materials in the treatment of oral diseases, point out the existing limitations, and speculate the prospects for clinical applications.
CONCLUSIONS: Our findings may provide useful information of stimuli-responsive materials in oral diseases for dental clinicians.

In situ self-assembly in living systems is referred to as the processes that regulate assembly by stimuli-responsive reactions at target sites under physiological conditions. Due to the advantages of precisely forming well-defined nanostructures at pathological lesions, in situ-formed assemblies with tailored bioactivity are promising for the development of next-generation biomedical agents. In this Perspective, we summarize the progress of in situ self-assembly of peptides in living cells with an emphasis on the state-of-the-art strategies regulating assembly processes, establishing complexity within assembly systems, and exploiting their applications in biomedicines. We also provide our forward conceiving perspectives on the challenges in the development of in situ assembly in living cells to demonstrate its great potential in creating biomaterials for healthcare in the future.

Cancer remains a significant challenge in extending human life expectancy in the 21st century, with staggering numbers projected by the International Agency for Research on Cancer for upcoming years. While conventional cancer therapies exist, their limitations, in terms of efficacy and side effects, demand the development of novel treatments that selectively target cancer cells. Tumor immunotherapy has emerged as a promising approach, but low response rates and immune-related side effects present significant clinical challenges. Researchers have begun combining immunotherapy with nanomaterials to optimize tumor-killing effects. Stimuli-responsive nanomaterials have become a focus of cancer immunotherapy research due to their unique properties. These nanomaterials target specific signals in the tumor microenvironment, such as pH or temperature changes, to precisely deliver therapeutic agents and minimize damage to healthy tissue. This article reviews the recent developments and clinical applications of endogenous and exogenous stimuli-responsive nanomaterials for tumor immunotherapy, analyzing the advantages and limitations of these materials and highlighting their potential for enhancing the immune response to cancer and improving patient outcomes.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints. It is one of the major causes of disability and morbidity worldwide. Administration of conventional drugs through the systemic route restricts the bioavailability of drugs, systemic toxicity, and reduced efficacy. We have introduced Rebamipide (Reb)-loaded Sinapic acid (SA)-Pullulan (PL) nanomicelles (Reb@SA-PL NMs), a nanotechnology based drug delivery system for the treatment of inflammatory arthritis. PL is a polysaccharide obtained from the fungus Aureobasidium pullulans, and SA is a bioactive polyphenol found in various plants. Both are classified by US-FDA Generally Recognised as Safe (GRAS) materials. Reb@SA-PL NMs found to be cytocompatible. Subsequently, intra-articular administration of Reb@SA-PL NMs enhances the anti-arthritic potential compared to free Reb drug in collagen-induced experimental inflammatory arthritis rat model. Reb@SA-PL NMs reduced the expression of RANKL receptor and Nf-κB. Reb@SA-PL NMs reverses the breakdown of type II collagen, MMP-13, and inhibits the pro-inflammatory markers. Reb@SA-PL NMs prevented bone erosion, cartilage degradation, joint oedema, and synovial inflammation. The results of the study demonstrated that Reb@SA-PL NMs, an enzyme-responsive drug delivery system, has excellent potential for alleviating inflammatory arthritis by blocking MMP-13 and RANKL.

Self-immolative chemistries that respond in an irreversible manner to external stimuli are highly attractive to permanently degrade filamentous supramolecular biomaterials. Within the monomer, a balance needs to be struck between its capacity to be supramolecularly polymerized and degraded at an appropriate rate for a given application. Herein, we unravel the structure-property-function relationships of a library of squaramide-based bolaamphiphiles bearing a central disulfide-based self-immolative spacer to construct supramolecular polymers responsive to a chemical stimulus in aqueous solutions. We examine the impact of changing the alkyl domain length (2 to 12 methylene units) on the formation of supramolecular filaments and their rate of degradation in response to a biological antioxidant, glutathione. A minimum of an octyl spacer is required to robustly form supramolecular polymers that can be irreversibly degraded through a cyclization-elimination reaction of the self-immolative spacer triggered by thiol-disulfide exchange within several hours. Further increasing the peripheral alkyl chain length to a decyl spacer increases the ordered packing of the amphiphiles, hindering their chemical degradation. This study provides a framework to design small molecule chemically responsive filamentous supramolecular polymers based on bolaamphiphilic monomers that can be irreversibly degraded in aqueous solutions for their eventual application as biomedical materials.

Chemotherapy as a common anticancer therapeutic modality is often challenged by various obstacles such as poor stability, low solubility, and severe side effects of chemotherapeutic agents as well as multidrug resistance of cancerous cells. Nanoparticles in the role of carriers for chemotherapeutic drugs and platforms for combining different therapeutic approaches have effectively participated in overcoming such drawbacks. In particular, nanoparticles able to induce their therapeutic effect in response to specific stimuli like tumor microenvironment characteristics (e.g., hypoxia, acidic pH, high levels of glutathione, and overexpressed hydrogen peroxide) or extrinsic stimulus of laser light bring about more precise and selective treatments. Among them, nanostructures of covalent organic frameworks (COFs) have drawn great interest in biomedical fields during recent years. Possessing large surface area, high porosity, structural stability, and customizable architecture, these biocompatible porous crystalline polymers properly translate to promising platforms for drug delivery and induction of combination therapies. With the focus on stimuli-responsive characteristics of nanoscale COFs, this study aims to propose an overview of their potentiality in cancer treatment on the basis of chemotherapy alone or in combination with sonodynamic, chemodynamic, photodynamic, and photothermal therapies.

The dynamic behaviour of metal-ligand bonding cultivates stimuli-mediated structural transformations in self-assembled molecular architectures. The propensity of synthetically designed self-assembled systems to interchange between higher-order architectures is increased multi-fold when the building blocks have higher conformational degrees of freedom. Herein, we report a new ligand, (2,7-bis(di(pyridin-4-yl)amino)-9H-fluoren-9-one) (L), which, upon self-assembly with a cis-[(ethylene-1,2-diamine)Pd(NO3)2] acceptor (M), resulted in the formation of a M6L3 trifacial barrel (C1) in water. Interestingly, during crystallization, a rare M12L6 triangular orthobicupola architecture (C2) was generated along with C1. C2 could also be generated in solution via the application of several stimuli. C1 in aqueous medium could stabilize one trans-stilbene (tS) or cis-stilbene (cS) molecule in its cavity, with a selectivity for the former from their mixture. Moreover, C1 acted as an effective host to prevent the otherwise facile photoisomerization of tS to cS inside its hydrophobic cavity under UV irradiation. Conversely, the visible-light-induced reverse isomerization of encapsulated cS to encapsulated tS could be achieved readily due to the better stabilization of tS within the cavity of C1 and its transparency to visible light. A multi-functional system was therefore designed, which at the same time is stimuli-responsive, shows isomer selectivity, and photo-protects trans-stilbene.

The solid tumors provide a series of biological barriers in cellular microenvironment for designing drug delivery methods based on advanced stimuli-responsive materials. These intertumoral and intratumoral barriers consist of perforated endotheliums, tumor cell crowding, vascularity, lymphatic drainage blocking effect, extracellular matrix (ECM) proteins, hypoxia, and acidosis. Triggering opportunities have been drawn for solid tumor therapies based on single and dual stimuli-responsive drug delivery systems (DDSs) that not only improved drug targeting in deeper sites of the tumor microenvironments, but also facilitated the antitumor drug release efficiency. Single and dual stimuli-responsive materials which are known for their lowest side effects can be categorized in 17 main groups which involve to internal and external stimuli anticancer drug carriers in proportion to microenvironments of targeted solid tumors. Development of such drug carriers can circumvent barriers in clinical trial studies based on their superior capabilities in penetrating into more inaccessible sites of the tumor tissues. In recent designs, key characteristics of these DDSs such as fast response to intracellular and extracellular factors, effective cytotoxicity with minimum side effect, efficient permeability, and rate and location of drug release have been discussed as core concerns of designing paradigms of these materials.