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Micro- and nanorobots excel in navigating the intricate and often inaccessible areas of the human body, offering immense potential for applications such as disease diagnosis, precision drug delivery, detoxification, and minimally invasive surgery. Despite their promise, practical deployment faces hurdles, including achieving stable propulsion in complex in vivo biological environments, real-time imaging and localization through deep tissue, and precise remote control for targeted therapy and ensuring high therapeutic efficacy. To overcome these obstacles, we introduce a hydrogel-based, imaging-guided, bioresorbable acoustic microrobot (BAM) designed to navigate the human body with high stability. Constructed using two-photon polymerization, a BAM comprises magnetic nanoparticles and therapeutic agents integrated into its hydrogel matrix for precision control and drug delivery. The microrobot features an optimized surface chemistry with a hydrophobic inner layer to substantially enhance microbubble retention in biofluids with multiday functionality and a hydrophilic outer layer to minimize aggregation and promote timely degradation. The dual-opening bubble-trapping cavity design enables a BAM to maintain consistent and efficient acoustic propulsion across a range of biological fluids. Under focused ultrasound stimulation, the entrapped microbubbles oscillate and enhance the contrast for real-time ultrasound imaging, facilitating precise tracking and control of BAM movement through wireless magnetic navigation. Moreover, the hydrolysis-driven biodegradability of BAMs ensures its safe dissolution after treatment, posing no risk of long-term residual harm. Thorough in vitro and in vivo experimental evidence demonstrates the promising capabilities of BAMs in biomedical applications. This approach shows promise for advancing minimally invasive medical interventions and targeted therapeutic delivery.

Autonomous nanorobots represent an advanced tool for precision therapy to improve therapeutic efficacy. However, current nanorobotic designs primarily rely on inorganic materials with compromised biocompatibility and limited biological functions. Here, we introduce enzyme-powered bacterial outer membrane vesicle (OMV) nanorobots. The immobilized urease on the OMV membrane catalyzes the decomposition of bioavailable urea, generating effective propulsion for nanorobots. This OMV nanorobot preserves the unique features of OMVs, including intrinsic biocompatibility, immunogenicity, versatile surface bioengineering for desired biofunctionalities, capability of cargo loading and protection. We present OMV-based nanorobots designed for effective tumor therapy by leveraging the membrane properties of OMVs. These involve surface bioengineering of robotic body with cell-penetrating peptide for tumor targeting and penetration, which is further enhanced by active propulsion of nanorobots. Additionally, OMV nanorobots can effectively safeguard the loaded gene silencing tool, small interfering RNA (siRNA), from enzymatic degradation. Through systematic in vitro and in vivo studies using a rodent model, we demonstrate that these OMV nanorobots substantially enhanced siRNA delivery and immune stimulation, resulting in the utmost effectiveness in tumor suppression when juxtaposed with static groups, particularly evident in the orthotopic bladder tumor model. This OMV nanorobot opens an inspiring avenue to design advanced medical robots with expanded versatility and adaptability, broadening their operation scope in practical biomedical domains., Competing Interests: Competing interests statement:The authors declare no competing interest.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo + self-assembly composed of azobenzene derivatives (Azo + ) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis -Azo + -mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo , including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo + molecules and loaded molecules. Conversely, visible light induces trans -Azo + formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Dynamic manipulation of supramolecular self-assembled structures is achieved irreversibly or under non-physiological conditions, thereby limiting their biomedical, environmental, and catalysis applicability. In this study, microgels composed of azobenzene derivatives stacked via π-cation and π-π interactions are developed that are electrostatically stabilized with Arg-Gly-Asp (RGD)-bearing anionic polymers. Lateral swelling of RGD-bearing microgels occurs via cis-azobenzene formation mediated by near-infrared-light-upconverted ultraviolet light, which disrupts intermolecular interactions on the visible-light-absorbing upconversion-nanoparticle-coated materials. Real-time imaging and molecular dynamics simulations demonstrate the deswelling of RGD-bearing microgels via visible-light-mediated trans-azobenzene formation. Near-infrared light can induce in situ swelling of RGD-bearing microgels to increase RGD availability and trigger release of loaded interleukin-4, which facilitates the adhesion structure assembly linked with pro-regenerative polarization of host macrophages. In contrast, visible light can induce deswelling of RGD-bearing microgels to decrease RGD availability that suppresses macrophage adhesion that yields pro-inflammatory polarization. These microgels exhibit high stability and non-toxicity. Versatile use of ligands and protein delivery can offer cytocompatible and photoswitchable manipulability of diverse host cells., (© 2022 Wiley-VCH GmbH.)

Surface functionalization of nanoparticles with polyethylene glycol (PEG) has been widely demonstrated as an anti-opsonization strategy to reduce protein corona formation which is one of the major concerns affecting target receptor recognition. However, excessive surface passivation with PEG can lead to the strong inhibition of cellular uptake and less efficient binding to target receptors, resulting in reduced potential of targeted delivery. To improve specific cell targeting while reducing the nonspecific protein adsorption, a secondary packaging of the nanoparticles with shorter PEG chains, making the targeting ligands densely stretched out for enhanced molecular recognition is demonstrated. Particularly, we report the tailored surface functionalization of the porous nanoparticles that require the stealth shielding onto the open-pore region. This study shows that, in addition to the surface chemistry, the conformation of the PEG layers controls the cellular interaction of nanoparticles. Since the distance between neighboring PEG chains determines the structural conformation of the grafted PEG molecules, tailored PEG combinations can efficiently resist the adsorption of serum proteins onto the pores by transitioning the conformation of the PEG chains, thus significantly enhance the targeting efficiency (>5-fold). The stretched brush PEG conformation with secondary packaging of shorter PEG chains could be a promising anti-opsonization and active targeting strategy for efficient intracellular delivery of nanoparticles.

Afterglow is superior to other optical modalities for biomedical applications in that it can exclude the autofluorescence background. Nevertheless, afterglow has rarely been applied to the high-contrast "off-to-on" activatable sensing scheme because the complicated afterglow systems hamper the additional inclusion of sensory functions while preserving the afterglow luminescence. Herein, a simple formulation of a multifunctional components-incorporated afterglow nanosensor (MANS) is developed for the superoxide-responsive activatable afterglow imaging of cisplatin-induced kidney injury. A multifunctional iridium complex (Ir-OTf) is designed to recover its photoactivities (phosphorescence and the ability of singlet oxygen-generating afterglow initiator) upon exposure to superoxide. To construct the nanoscopic afterglow detection system (MANS), Ir-OTf is incorporated with another multifunctional molecule (rubrene) in the polymeric micellar nanoparticle, where rubrene also plays dual roles as an afterglow substrate and a luminophore. The multiple functions covered by Ir-OTf and rubrene renders the composition of MANS quite simple, which exhibits superoxide-responsive "off-to-on" activatable afterglow luminescence for periods longer than 11 min after the termination of pre-excitation. Finally, MANS is successfully applied to the molecular imaging of cisplatin-induced kidney injury with activatable afterglow signals responsive to pathologically overproduced superoxide in a mouse model without autofluorescence background., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)

Hybrid nanostructures are promising for ultrasound-triggered drug delivery and treatment, called sonotheranostics. Structures based on plasmonic nanoparticles for photothermal-induced microbubble inflation for ultrasound imaging exist. However, they have limited therapeutic applications because of short microbubble lifetimes and limited contrast. Photochemistry-based sonotheranostics is an attractive alternative, but building near-infrared (NIR)-responsive echogenic nanostructures for deep tissue applications is challenging because photolysis requires high-energy (UV-visible) photons. Here, we report a photochemistry-based echogenic nanoparticle for in situ NIR-controlled ultrasound imaging and ultrasound-mediated drug delivery. Our nanoparticle has an upconversion nanoparticle core and an organic shell carrying gas generator molecules and drugs. The core converts low-energy NIR photons into ultraviolet emission for photolysis of the gas generator. Carbon dioxide gases generated in the tumor-penetrated nanoparticle inflate into microbubbles for sonotheranostics. Using different NIR laser power allows dual-modal upconversion luminescence planar imaging and cross-sectional ultrasonography. Low-frequency (10 MHz) ultrasound stimulated microbubble collapse, releasing drugs deep inside the tumor through cavitation-induced transport. We believe that the photoechogenic inflatable hierarchical nanostructure approach introduced here can have broad applications for image-guided multimodal theranostics.

Indocyanine green (ICG) is a clinically approved dye that has shown great promise as a phototheranostic material with fluorescent, photoacoustic and photothermal responses in the near-infrared region. However, it has certain limitations, such as poor photostability and non-specific binding to serum proteins, subjected to rapid clearance and decreased theranostic efficacy in vivo. This study reports stable and biocompatible nanoparticles of ICG (ICG-Fe NPs) where ICG is electrostatically complexed with an endogenously abundant metal ion (Fe 3+ ) and subsequently nanoformulated with a clinically approved polymer surfactant, Pluronic F127. Under near-infrared laser irradiation, ICG-Fe NPs were found to be more effective for photothermal temperature elevation than free ICG molecules owing to the improved photostability. In addition, ICG-Fe NPs showed the markedly enhanced tumor targeting and visualization with photoacoustic/fluorescent signaling upon intravenous injection, attributed to the stable metal complexation that prevents ICG-Fe NPs from releasing free ICG before tumor targeting. Under dual-modal imaging guidance, ICG-Fe NPs could successfully potentiate photothermal therapy of cancer by applying near-infrared laser irradiation, holding potential as a promising nanomedicine composed of all biocompatible ingredients for clinically relevant phototheranostics., (© 2021. The Author(s).)

Since oxidative stress has been recognized as a major factor contributing to the progression of several neurodegenerative disorders, reactive oxygen species (ROS) including superoxide have received great attention as a representative molecular marker for the diagnosis of Alzheimer's disease (AD). Here, superoxide-sensitive fluorogenic molecular probes, benzenesulfonylated resorufin derivatives (BSRs), were newly devised for optical bioimaging of oxidative events in neurodegenerative processes. BSRs, fluorescence-quenched benzenesulfonylated derivatives of resorufin, were designed to recover their fluorescence upon exposure to superoxide through a selective nucleophilic uncaging reaction of the benzenesulfonyl cage. Among BSRs, BSR6 presented the best sensitivity and selectivity to superoxide likely due to the optimal reactivity matching between the nucleophilicity of superoxide and its electrophilicity ascribed to the highly electron-withdrawing pentafluoro-substitution on the benzenesulfonyl cage. Fluorescence imaging of inflammatory cells and animal models presented the potential of BSR6 for optical sensing of superoxide in vitro and in vivo. Furthermore, microglial cell (Bv2) imaging with BSR6 enabled the optical monitoring of intracellular oxidative events upon treatment with an oxidative stimulus (amyloid beta, Aβ) or the byproduct of oxidative stress (4-hydroxynonenal, HNE).

With increasing ozone depletion, ultraviolet (UV) exposure from sunlight has become a significant health risk. Although commercially available sun protectants provide reasonable protection, they have limitations in terms of safety and aesthetics. Here, we have developed biocompatible and biodegradable sunscreens by facile synthesis of organosilica nanoparticles (o-SNPs) with self-encapsulated phenyl motifs using phenylsilane precursors. The physical structure of o-SNPs is elaborately controlled such that they are large enough to reflect UVA but small enough to be imperceptible when applied on the skin. The chemically attached phenyl motifs to o-SNPs facilitate filtering UVB via their delocalized π-orbitals. The o-SNPs generate a negligible amount of reactive oxygen species under UV exposure. Ex vivo two-photon microscopy reveals that the o-SNPs tend to adhere to the outer layers of skin without further intradermal penetration, resulting in less skin irritation. In vivo UV protection tests confirmed the excellent sunscreen effect of o-SNPs compared with conventional organic and inorganic UV filters.

Porous silicon nanoparticles (PSiNPs) have attracted increasing interest as biomedical probes for drug delivery and imaging. In particular, a set of unique properties including biodegradability, intrinsic photoluminescence, and favorable mesoporous structure providing high drug loading allow PSiNPs to address current challenges of translational nanomedicine. In this review, the important features of PSiNPs considered as a biomedical imaging probe will be concisely discussed along with recent advances in fabrication and theranostic applications. Firstly, an overview of PSiNP fabrication with controllable geometry through top-down or bottom-up strategies is provided. Next, intrinsic photoluminescence, the key element allowing application of PSiNPs as an imaging agent, is highlighted with near-infrared emission and micro-second scale lifetime. Emerging technologies for biodegradable nanomedicine based on PSiNPs are then presented. Advances of PSiNPs for disease treaments including photodynamic and photothermal therapeutics are also discussed to open up potential translational medical strategies. In addition, the versatile surface chemistry and modification of PSiNPs in the context of biomedical applications are extensively discussed. Overall, the promising characteristics of PSiNPs encourage further exploration for biomedical research and translational medical platforms, particularly in biomedical imaging.

In this article, we demonstrate that TiO 2 @carbon core/shell (TiO 2 @C) nanocomposite photocatalysts prepared by carbonizing a single molecular layer of aromatic compounds adsorbed on the surface of TiO 2 nanoparticles selectively enhance the generation of hydrogen peroxide (H 2 O 2 ). Atomically thin carbon shells have been formed directly on the surface of TiO 2 nanoparticles through pyrolytic decarboxylation of the adsorbed aromatic compounds, benzoic acid (BA), and 1-naphthoic acid (NA), which yields two types of TiO 2 @C nanocomposites, TiO 2 @C(BA) and TiO 2 @C(NA). Raman spectroscopy shows that the as-obtained nanocomposites have similar degrees of graphitization (D/G band ratio), regardless of the type of aromatic precursors, but TiO 2 @C(NA) contains more oxygenic species than TiO 2 @C(BA) (D*/G band ratio). Such oxygenic species predominantly exist in the form of epoxide groups, as determined by attenuated total reflection infrared spectroscopy. The sp 2 carbon atoms near the epoxide groups in the carbon shell can act as active sites for the two-electron reduction of O 2 . Therefore, TiO 2 @C(NA) can generate H 2 O 2 more efficiently than TiO 2 @C(BA). Furthermore, the carbon shells retard the reconsumption of the generated H 2 O 2 by inhibiting the adsorption of H 2 O 2 on the surface of TiO 2 nanoparticles, thereby improving the photocatalytic efficiency of H 2 O 2 generation. Finally, we have shown the durability and reproducibility of our TiO 2 @C-based photocatalytic systems. We believe that our research may offer a potentially improved strategy for H 2 O 2 generation and other photocatalytic applications.

With biocompatibility, biodegradability, and high functionality, silica nanoparticles (SNPs) have been widely investigated for various biomedical applications. However, lack of optical fluorescence has limited the application of SNPs as a degradable imaging agent. Here, we hydrothermally synthesized fluorescent SNPs by artificially generating optically active defect centers using tetraethyl orthosilicate and (3-aminopropyl)trimethoxysilane. The synthesized SNPs demonstrated strong blue photoluminescence originating from the dioxasilyrane (=Si(O 2 )) and silylene (=Si:) defect centers with the aid of aminopropyl groups. Furthermore, phosphorescence was observed at 459 nm, indicating the presence of silylene in SNPs. Finally, these SNPs have been successfully utilized as a fluorescent probe for bioimaging of normal, cancer, and macrophage cells.

Challenges exist in taking advantage of dye molecules for reliable and reproducible molecular probes in biomedical applications. In this study, we show how to utilize the dye molecules for bioimaging within protective carriers of nanocrystalline metal-organic frameworks (nMOFs) particles. Specifically, Resorufin and Rhodamine-6G having different molecular sizes were encapsulated within close-fitting pores of nMOF-801 and nUiO-67 particles, respectively. The resulting nanocrystalline particles have high crystallinity, uniform size, and morphology and preserve enhanced photoluminescence properties with exceptional stabilities in biomedical environment. The samples are further functionalized with a targeting agent and successfully work for fluorescence imaging of FL83B (human hepatocyte cell) and HepG2 (human hepatocellular carcinoma) without cytotoxicity.