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Stimuli-activatable strategies prevail in the design of nanomedicine for cancer theranostics. Upon exposure to endogenous/exogenous stimuli, the stimuli-activatable nanomedicine could be self-assembled, disassembled, or functionally activated to improve its biosafety and diagnostic/therapeutic potency. A myriad of tumor-specific features, including a low pH, a high redox level, and overexpressed enzymes, along with exogenous physical stimulation sources (light, ultrasound, magnet, and radiation) have been considered for the design of stimuli-activatable nano-medicinal products. Recently, novel stimuli sources have been explored and elegant designs emerged for stimuli-activatable nanomedicine. In addition, multi-functional theranostic nanomedicine has been employed for imaging-guided or image-assisted antitumor therapy. In this review, we rationalize the development of theranostic nanomedicine for clinical pressing needs. Stimuli-activatable self-assembly, disassembly or functional activation approaches for developing theranostic nanomedicine to realize a better diagnostic/therapeutic efficacy are elaborated and state-of-the-art advances in their structural designs are detailed. A reflection, clinical status, and future perspectives in the stimuli-activatable nanomedicine are provided.

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Using fMRI, precise temporal control was extracted from routine activities in a female blind subject. Findings reveal a specific neural machinery for temporal control of recalled sequential events in episodic memory.

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Kidney disease is one of the most life-threatening health problems, affecting millions of people in the world. Commonly used steroids and immunosuppressants often fall exceptionally short of outcomes with inescapable systemic toxicity. With the booming research in nanobiotechnology, stimuli-responsive nanoplatform has come an appealing therapeutic strategy for kidney disease. Endogenous stimuli-responsive materials have shown profuse promise owing to their enhanced spatiotemporal control and precise to the location of the lesion. This review focuses on recent advances stimuli-responsive drug delivery nano-architectonics for kidney disease. First, a brief introduction of pathogenesis of kidney disease and pathological microenvironment were provided. Then, various endogenous stimulus involved in drug delivery nanoplatforms including pH, ROS, enzymes, and glucose were categorized based on the pathological mechanisms of kidney disease. Next, we separately summarized literature examples of endogenous stimuli-responsive nanomaterials, and outlined the design strategies and response mechanisms. Finally, the paper was concluded by discussing remaining challenges and future perspectives of endogenous stimuli-responsive drug delivery nanoplatform for expediting the speed of development and clinical applications.

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In recent years, the functionalization of mesoporous silica nanoparticles (MSNs) with different types of responsive pore gatekeepers have shown great potential for the formulation of drug delivery systems (DDS) with minimal premature leakage and site-specific controlled release. New nanotechnological approaches have been developed with the objective of utilizing natural biopolymers as smart materials in drug delivery applications. Natural biopolymers are sensitive to various physicochemical and biological stimuli and are endowed with intrinsic biodegradability, biocompatibility, and low immunogenicity. Their use as biocompatible smart coatings has extensively been investigated in the last few years. This review summarizes the MSNs coating procedures with natural polysaccharides and protein-based biopolymers, focusing on their application as responsive materials to endogenous stimuli. Biopolymer-coated MSNs, which conjugate the nanocarrier features of mesoporous silica with the biocompatibility and controlled delivery provided by natural coatings, have shown promising therapeutic outcomes and the potential to emerge as valuable candidates for the selective treatment of various diseases.

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Medication in arthritis therapies is complex because the inflammatory progression of rheumatoid arthritis (RA) and osteoarthritis (OA) is intertwined and influenced by one another. To address this problem, drug delivery systems (DDS) are composed of four independent exogenous triggers and four dependent endogenous stimuli that are controlled on program and induced on demand, respectively. However, the relationships between the mechanisms of endogenous stimuli and exogenous triggers with pathological alterations remain unclear, which results in a major obstacle in terms of clinical translation. Thus, the rationale for designing a guidance system for these mechanisms via their key irritant biosensors is in high demand. Many approaches have been applied, although successful clinical translations are still rare. Through this review, the status quo in historical development is highlighted in order to discuss the unsolved clinical difficulties such as infiltration, efficacy, drug clearance, and target localisation. Herein, we summarise and discuss the rational compositions of exogenous triggers and endogenous stimuli for programmable therapy. This advanced active pharmaceutical ingredient (API) implanted dose allows for several releases by remote controls for endogenous stimuli during lesion infections. This solves the multiple implantation and local toxic accumulation problems by using these flexible desired releases at the specified sites for arthritis therapies.

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Cancer is complicated to treat because of its high propensity for recurrence and metastasis, and various side effects of conventional cancer treatments. With the development of nanotechnology, biology, material science and pharmacy, nanoparticles emerge as a promising method to load anti-cancer drugs to deal with the downsides of conventional treatments. Among the various class of nanoparticles, endogenous stimuli-responsive nanoparticles exert significant anti-cancer effects by releasing drugs due to the stimulations from pH gradient, redox as well as other enzymes of cancer microenvironment. Extraordinary progress has been achieved as the latest endogenous stimuli-responsive nanoparticles exhibit better therapeutic effects, lower toxicity, and superior biocompatibility, indicating brighter prospects for cancer therapy. However, these stimuli-responsive nanoparticles are still not ready for large-scale clinical application, due to reasons such as the lack of clinical trials and high cost of manufacturing. Here, we consolidate the advancements and limitations of various endogenous stimuli-responsive nanoparticles, as well as critically discuss the prospects of this kind of nanoparticles in tumor treatments.

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Stimuli-responsive drug-delivery systems (DDSs) have emerged as a potential tool for applications in healthcare, mainly in the treatment of cancer where versatile nanocarriers are co-triggered by endogenous and exogenous stimuli. Two-dimensional (2D) cell cultures are the most important in vitro model used to evaluate the anticancer activity of these stimuli-responsive DDSs due to their easy manipulation and versatility. However, some limitations suggest that these in vitro models poorly predict the outcome of in vivo studies. One of the main drawbacks of 2D cell cultures is their inadequate representation of the 3D environment's physiological complexity, which sees cells interact with each other and the extracellular matrix (ECM) according to their specific cellular organization. In this regard, 3D cancer models are a promising approach that can overcome the main shortcomings of 2D cancer cell cultures, as these in vitro models possess many peculiarities by which they mimic in vivo tumors, including physiologically relevant cell-cell and cell-ECM interactions. This is, in our opinion, even more relevant when a stimuli-responsive DDS is being investigated. In this review, we therefore report and discuss endogenous and exogenous stimuli-responsive DDSs whose effectiveness has been tested using 3D cancer cell cultures.

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Though numerous external-stimuli-triggered tumor therapies, including phototherapy, radiotherapy, and sonodynamic therapy have made great progress in cancer therapy, the low penetration depth of the laser, safety concerns of radiation, the therapeutic resistance, and the spatio-temporal constraints of the specific equipment restrict their convenient clinical applications. What is more, the inherent physiological barriers of the tumor microenvironment (TME), including hypoxia, heterogeneity, and high expression of antioxidant molecules also restrict the efficiency of tumor therapy. As a result, the development of nanoplatforms responsive to endogenous stimuli (such as glucose, acidic pH, cellular redox events, and etc.) has attracted great attention for starvation therapy, ion therapy, prodrug-mediated chemotherapy, or enzyme-catalyzed therapy. In addition, nanomedicines can be modified by some targeted units for precisely locating in subcellular organelles and boosting the destroying of tumor tissue, decreasing the dosage of nanoagents, reducing side effects, and enhancing the therapeutic efficiency. Herein, the properties of the TME, the advantages of endogenous stimuli, and the principles of subcellular-organelle-targeted strategies will be emphasized. Some necessary considerations for the exploitation of precision medicine and clinical translation of multifunctional nanomedicines in the future are also pointed out.

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To achieve the promise of stimuli-responsive drug delivery systems for the treatment of cancer, they should (1) avoid premature clearance; (2) accumulate in tumors and undergo endocytosis by cancer cells; and (3) exhibit appropriate stimuli-responsive release of the payload. It is challenging to address all of these requirements simultaneously. However, the numerous proof-of-concept studies addressing one or more of these requirements reported every year have dramatically expanded the toolbox available for the design of drug delivery systems. This review highlights recent advances in the targeting and stimuli-responsiveness of drug delivery systems. It begins with a discussion of nanocarrier types and an overview of the factors influencing nanocarrier biodistribution. On-demand release strategies and their application to each type of nanocarrier are reviewed, including both endogenous and exogenous stimuli. Recent developments in stimuli-responsive targeting strategies are also discussed. The remaining challenges and prospective solutions in the field are discussed throughout the review, which is intended to assist researchers in overcoming interdisciplinary knowledge barriers and increase the speed of development. This review presents a nanocarrier-based drug delivery systems toolbox that enables the application of techniques across platforms and inspires researchers with interdisciplinary information to boost the development of multifunctional therapeutic nanoplatforms for cancer therapy.

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In the past few decades, polymeric nanocarriers have been recognized as promising tools and have gained attention from researchers for their potential to efficiently deliver bioactive compounds, including drugs, proteins, genes, nucleic acids, etc., in pharmaceutical and biomedical applications. Remarkably, these polymeric nanocarriers could be further modified as stimuli-responsive systems based on the mechanism of triggered release, i.e., response to a specific stimulus, either endogenous (pH, enzymes, temperature, redox values, hypoxia, glucose levels) or exogenous (light, magnetism, ultrasound, electrical pulses) for the effective biodistribution and controlled release of drugs or genes at specific sites. Various nanoparticles (NPs) have been functionalized and used as templates for imaging systems in the form of metallic NPs, dendrimers, polymeric NPs, quantum dots, and liposomes. The use of polymeric nanocarriers for imaging and to deliver active compounds has attracted considerable interest in various cancer therapy fields. So-called smart nanopolymer systems are built to respond to certain stimuli such as temperature, pH, light intensity and wavelength, and electrical, magnetic and ultrasonic fields. Many imaging techniques have been explored including optical imaging, magnetic resonance imaging (MRI), nuclear imaging, ultrasound, photoacoustic imaging (PAI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). This review reports on the most recent developments in imaging methods by analyzing examples of smart nanopolymers that can be imaged using one or more imaging techniques. Unique features, including nontoxicity, water solubility, biocompatibility, and the presence of multiple functional groups, designate polymeric nanocues as attractive nanomedicine candidates. In this context, we summarize various classes of multifunctional, polymeric, nano-sized formulations such as liposomes, micelles, nanogels, and dendrimers.

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BACKGROUND: Nanoparticle technologies used for human administration must be designed to interact with a living host environment. The idea about bioinspired smart drug delivery carriers includes the development of biocompatible nanomaterials which can be further loaded with the drug for specific targeted drug delivery applications. OBJECTIVE: Biosmart nanosystems are used for several applications in the delivery of drugs and pharmaceuticals for their therapeutic applications like biological markers, diagnostic purposes such as imaging applications and also for gene therapy. Thus, the bioinspired nanocarriers are capable of carrying biologically active molecules to the target sites. This bioinspired nanosystem constitutes of lipids, polymers and biomaterials which utilizes various responsive sensors for targeted drug delivery systems. However, external conditions such as heat, light, magnetic or electric field and ultrasounds, along with temperature, altered pH and ionic strength can affect the bioinspired smart nanosystem for drug delivery. CONCLUSION: The present review focuses on challenges for the development of bioinspired smart nanocarriers for the management of various disorders.

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There is ample evidence that biodegradable polyelectrolyte nanocapsules are multifunctional vehicles which can smuggle drugs into cells, and release them upon endogenous activation. A large number of endogenous stimuli have already been tested in vitro, and in vivo research is escalating. Thus, the interest in the design of intelligent polyelectrolyte multilayer (PEM) drug delivery systems is clear. The need of the hour is a systematic translation of PEM-based drug delivery systems from the lab to clinical studies. Reviews on multifarious stimuli that can trigger the release of drugs from such systems already exist. This review summarizes the available literature, with emphasis on the recent progress in PEM-based drug delivery systems that are receptive in the presence of endogenous stimuli, including enzymes, glucose, glutathione, pH, and temperature, and addresses different active and passive drug targeting strategies. Insights into the current knowledge on the diversified endogenous approaches and methodological challenges may bring inspiration to resolve issues that currently bottleneck the successful implementation of polyelectrolytes into the catalog of third-generation drug delivery systems.

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As we learn more about the biology of the Toll-like receptors (TLRs), a wide range of molecules that can activate this fascinating family of pattern recognition receptors emerges. In addition to conserved pathogenic components, endogenous danger signals created upon tissue damage are also sensed by TLRs. Detection of these types of stimuli results in TLR mediated inflammation that is vital to fight pathogenic invasion and drive tissue repair. Aberrant activation of TLRs by pathogenic and endogenous ligands has also been linked with the pathogenesis of an increasing number of infectious and autoimmune diseases, respectively. Most recently, allergen activation of TLRs has also been described, creating a third broad class of TLR stimulus that has helped to shed light on the pathogenesis of allergic disease. To date, microbial activation of TLRs remains best characterized. Each member of the TLR family senses a specific subset of pathogenic ligands, pathogen associated molecular patterns (PAMPS), and a wealth of structural and biochemical data continues to reveal the molecular mechanisms of TLR activation by PAMPs, and to demonstrate how receptor specificity is achieved. In contrast, the mechanisms by which endogenous molecules and allergens activate TLRs remain much more mysterious. Here, we provide an overview of our current knowledge of how very diverse stimuli activate the same TLRs and the structural basis of these modes of immunity.

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