Force degradation of two orthodontic accessories analyzed in vivo and in vitro.

OBJECTIVE: To compare force degradation of elastomeric chains and NiTi coil springs in vivo and in vitro, and evaluate the effects of pre-stretched and reused elastomeric chains in the oral cavity during the time. METHODS: In the in vitro groups, 4-unit elastomeric chains and NiTi coil springs with an initial force of 200 g were placed in dry air and artificial saliva. The volunteers wore clear retainers which were used to hold the sample of 4-unit chains, pre-stretched 4-unit chains, and NiTi coil springs with the initial force of 200 g in the in vivo groups. After the first 4 weeks, 4-unit specimens were stretched to 200 g again for another 4 weeks in vivo. The force value and the percentage of force degradation were recorded at each measurement time interval in the in vivo and in vitro groups. RESULTS: The force degradation of elastomeric chains was greatest within the initial 4 hours, followed by a more stable phase after 1 week. The average force degradation of 4-unit elastomeric chains after 4 weeks was in vivo (64.8%) > artificial saliva (55.0%) > dry air (46.42%) (P < 0.05). The force degradation of NiTi coil springs in vivo (15.36%) or in artificial saliva (15.8%) was greater than in dry air (7.6%) (P < 0.05). NiTi coil springs presented a gentler force decay than elastomeric chains during the period (P < 0.05). In vivo, the force degradation of pre-stretched and reused elastomeric chains decreased less than the regular style(P < 0.05). CONCLUSION: The force degradation of the elastomeric chains and NiTi coil springs varied in different environments. NiTi coil springs presented a gentler force decay than elastomeric chains during the period. Orthodontists should consider the force degradation characteristics of orthodontic accessories in clinical practice.

Camouflaged Virus-Like-Nanocarrier with a Transformable Rough Surface for Boosting Drug Delivery.

Due to non-specific strong nano-bio interactions, it is difficult for nanocarriers with permanent rough surface to cross multiple biological barriers to realize efficient drug delivery. Herein, a camouflaged virus-like-nanocarrier with a transformable rough surface is reported, which is composed by an interior virus-like mesoporous SiO2 nanoparticle with a rough surface (vSiO2 ) and an exterior acid-responsive polymer. Under normal physiological pH condition, the spikes on vSiO2 are hidden by the polymer shell, and the non-specific strong nano-bio interactions are effectively inhibited. While in the acidic tumor microenvironment, the nanocarrier sheds the polymer camouflage to re-expose its rough surface. So, the retention ability and endocytosis efficiency of the nanocarrier are great improved. Owing to it's the dynamically variable rough surface, the rationally designed nanocarrier exhibits extended blood-circulation-time and enhanced tumor accumulation.

Deciphering the Fingerprint of Dissolved Organic Matter in the Soil Amended with Biodegradable and Conventional Microplastics Based on Optical and Molecular Signatures.

Biodegradable polymers are promoted as promising alternatives for conventional non-degradable plastics, but they may also negatively impact soil ecosystems. Here, we estimated the effects of biodegradable (polylactide (PLA) and polybutylene succinate (PBS)) and non-biodegradable (polyethylene (PE) and polystyrene (PS)) microplastics at a concentration of 1% (w/w) on dissolved organic matter (DOM) in two soil types, a black soil (BS) and a yellow soil (YS), by using fluorescence excitation-emission matrix spectroscopy and ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). PBS significantly increased the contents of soil dissolved organic carbon (DOC) and the relative intensities of protein-like components. The turnover rates of soil DOM were statistically higher in PBS treatments (0.106 and 0.196, p < 0.001) than those in other microplastic groups. The FT-ICR-MS results indicated that more labile-active DOM molecules were preferentially obtained in biodegradable microplastic treatments, which may be attributed to the polymer degradation. The conventional microplastics showed no significant effects on the optical characteristics but changed the molecular compositions of the soil DOM. More labile DOM molecules were observed in BS samples treated with PE compared to the control, while the conventional microplastics decreased the DOM lability in YS soil. The distinct priming effects of plastic-leached DOM may trigger the DOM changes in different soils. This study provided important information for further understanding the impact of microplastics on soil carbon processes.

Reversible Shielding between Dual Ligands for Enhanced Tumor Accumulation of ZnPc-Loaded Micelles.

Herein, we report a ligand-reversible-shielding strategy based on the mutual shielding of dual ligands tethered to the surface of nanoparticles. To exemplify this concept, phenylboronic acid-functionalized poly(ethylene glycol)- b-poly(ε-caprolactone) (PBA-PEG-PCL) and galactose-functionalized diblock polymer (Gal-PEG-PCL) were mixed to form dual-ligand micelles (PBA/Gal). PBA and Gal residues could form a complex at pH 7.4 and mutually shield their targeting function. At pH 6.8, the binding affinity between PBA and Gal weakened, and PBA preferred to bind with the sialic acid residues on the tumor cell surface rather than to Gal on the micellar surface; furthermore, the unbound Gal recovered its targeting ability toward the asialoglycoprotein receptor. When the pH decreased from 7.4 to 6.8, enzyme-linked immunosorbent assays exhibited that the percentage of exposed Gal on the micellar surface increased 1.9-fold, and flow cytometry showed that HepG2 cellular uptake increased 4.3-fold. More importantly, this process was reversible, confirming the reversible shielding and deshielding of dual ligands. With the encapsulation of a photosensitizer, zinc phthalocyanine (ZnPc), the reversible-shielding micelles showed a 48% improvement in the half-life ( t1/2) in blood circulation, a 54% decrease in liver capture, a 40% increase in tumor accumulation, and a 10.3% improvement in the tumor inhibition rate compared to the Gal-coated irreversible micelles. This dual-ligand mutual-shielding strategy provides a new perspective on reversible tumor targeting.

An effective and biocompatible polyethylenimine based vaginal suppository for gene delivery.

Gene therapy targeted human papillomavirus (HPV) is a promising treatment for cervical cancer, and the key for clinical application depends on an effective gene delivery method. Our aim was to formulate a new pharmaceutical formula for appropriate gene delivery intravaginally. For the first time, we here developed a new polyethylenimine (PEI) based vaginal suppository. The sectional immunofluorescence results confirmed the delivery efficacy both in vivo and in vitro. The quenching fluorescence and decreased gene expression in topical epithelium of green fluorescence protein (GFP) transgenic mice demonstrated the efficient targeting potential of the suppository. The other aim of this study was to evaluate the biocompatibility of the PEI based transfer. To our knowledge, this was also the first study to explore the toxicity in vivo systematically and comprehensively. Our study provided novel ideas for the translational application of PEI based suppository to the prevention and treatment of cervical cancer.

Intracellular and in Vivo Cyanide Mapping via Surface Plasmon Spectroscopy of Single Au-Ag Nanoboxes.

Cyanide is extremely toxic to organisms but difficult to detect in living biological specimens. Here, we report a new CN- sensing platform based on unmodified Au-Ag alloy nanoboxes that etch in the presence of this analyte, yielding a shift in plasmon frequency that correlates with the analyte concentration. Significantly, when combined with dark field microscopy, these particle probes can be used to measure CN- concentrations in HeLa cells and in vivo in Zebra fish embryos. The limit of detection (LOD) of the novel method is 1 nM (below the acceptable limit defined by the World Health Organization), and finite-difference time-domain (FDTD) calculations are used to understand the CN- induced spectral shifts.

Highly biocompatible zwitterionic phospholipids coated upconversion nanoparticles for efficient bioimaging.

The potential of upconversion nanoparticles (UCNPs) in various biomedical applications, including immunoassays, biomedical imaging, and molecular sensing, requires their surface derivatized to be hydrophilic and biocompatible. Here, a new family of compact zwitterionic ligand systems composed with functional phospholipids was designed and used for the surface modification of UCNPs. The zwitterionic UCNPs are hydrophilic, compact, and easily functionalized. It was proved that zwitterionic phospholipids could provide UCNPs with not only extended pH and salt stability but also little nonspecific interactions to positively and negatively charged proteins, low nonspecific adhesion in live-cell imaging process. Most notably, the efficient in vivo tumor imaging performance and long blood circulation half-life suggests the excellent biocompatibility for in vivo imaging of the zwitterionic UCNPs.

Epitaxial seeded growth of rare-earth nanocrystals with efficient 800 nm near-infrared to 1525 nm short-wavelength infrared downconversion photoluminescence for in†vivo bioimaging.

Novel ß-NaGdF4/Na(Gd,Yb)F4:Er/NaYF4:Yb/NaNdF4:Yb core/shell 1/shell 2/shell 3 (C/S1/S2/S3) multi-shell nanocrystals (NCs) have been synthesized and used as probes for in vivo imaging. They can be excited by near-infrared (800 nm) radiation and emit short-wavelength infrared (SWIR, 1525 nm) radiation. Excitation at 800 nm falls into the "biological transparency window", which features low absorption by water and low heat generation and is considered to be the ideal excitation wavelength with the least impact on biological tissues. After coating with phospholipids, the water-soluble NCs showed good biocompatibility and low toxicity. With efficient SWIR emission at 1525 nm, the probe is detectable in tissues at depths of up to 18 mm with a low detection threshold concentration (5 nM for the stomach of nude mice and 100 nM for the stomach of SD rats). These results highlight the potential of the probe for the in vivo monitoring of areas that are otherwise difficult to analyze.

Prenatal and postnatal exposure to polystyrene microplastics induces testis developmental disorder and affects male fertility in mice.

Polystyrene microplastics (PS-MPs) can threaten human health, especially male fertility. However, most existing studies have focused on the adulthood stage of male reproduction toxicity caused by relatively short-term PS-MP exposure. This study aimed to investigate the toxic effect of PS-MPs on testicular development and reproductive function upon prenatal and postnatal exposure. Pregnant mice and their offspring were exposed to 0, 0.5 mg/L, 5 mg/L, and 50 mg/L PS-MPs through their daily drinking water from gestational day 1 to postnatal day (PND) 35 or PND70. We found that PS-MP exposure induced testis development disorder by PND35 and spermatogenesis dysfunction by PND70. By combining RNA sequencing results and bioinformatics analysis, the hormone-mediated signaling pathway, G1/S transition of the mitotic cell cycle, coregulation of androgen receptor activity, and Hippo signaling pathway were shown to be involved in testis development on PND35. The meiotic cell cycle, regulation of the immune effector process, neutrophil degranulation, and inflammation mediated by chemokine and cytokine signaling pathways were associated with disturbed spermatogenesis on PND70. These findings show that prenatal and postnatal exposure to PS-MPs resulted in testis development disorder and male subfertility, which may be regulated by the Hippo signaling pathway and involve an immune reaction.

Denitrification performance and microbial community of bioreactor packed with PHBV/PLA/rice hulls composite.

In this study, a novel biodegradable PHBV/PLA/rice hulls (PPRH) composite was applied and tested as biofilm attachment carrier and carbon source in two bioreactors for biological denitrification process. The denitrification performance, effect of operational conditions and microbial community structure of PPRH biofilm were evaluated. The batch experiment results showed that PPRH-packed bioreactor could completely remove 50 mg L-1 of NO3--N at natural pH (ca. 7.5) and room temperature. The continuous flow experiments indicated that high NO3--N removal efficiency (77%-99%) was achieved with low nitrite (<0.48 mg L-1) and ammonia (<0.81 mg L-1) accumulation, when influent NO3--N concentration was 30 mg L-1 and hydraulic retention time was 2-6 h. Furthermore, the microbial community analysis indicated that bacteria belonging to genus Diaphorobacter in phylum Proteobacteria were the most dominant and major denitrifiers in denitrification. In summary, PPRH composite was a promising carbon source for biological nitrate removal from water and wastewater.

Effects of microplastics on soil microbiome: The impacts of polymer type, shape, and concentration.

Increasing research has recognized that the ubiquitous presence of microplastics in terrestrial environments is undeniable, which potentially alters the soil ecosystem properties and processes. The fact that microplastics with diverse characteristics enter into the soil may induce distinct effects on soil ecosystems. Our knowledge of the impacts of microplastics with different polymers, shapes, and concentrations on soil bacterial communities is still limited. To address this, we examined the effects of spherical microplastics (150 µm) with different polymers (i.e., polyethylene (PE), polystyrene (PS), and polypropylene (PP)) and four shapes of PP microplastics (i.e., fiber, film, foam, and particle) at a constant concentration (1%, w/w) on the soil bacterial community in an agricultural soil over 60 days. Treatments with different concentrations (0.01-20%, w/w) of PP microplastic particles (150 µm) were also included. The bacterial communities in PE and PP treatments showed a similar pattern but separated from those in PS-treated soils, indicating the polymer backbone structure is an important factor modulating the soil bacterial responses. Fiber, foam, and film microplastics significantly affected the soil bacterial composition as compared to the particle. The community dissimilarity of soil bacteria was significantly (R2 = 0.592, p < 0.001) correlated with the changes of microplastic concentration. The random forest model identified that certain bacteria belonging to Patescibacteria were closely linked to microplastic contamination. Additionally, analysis of the predicted function further showed that microplastics with different characteristics caused distinct effects on microbial community function. Our findings suggested that the idiosyncrasies of microplastics should not be neglected when studying their effects on terrestrial ecosystems.

Improving the functionality of chitosan-based packaging films by crosslinking with nanoencapsulated clove essential oil.

The study aimed to obtain chitosan composite films with gratifying physical and functional properties. First, we developed a Pickering emulsion containing clove essential oil (CEO)-loaded nanoparticles with 1:2 (w/w) zein and sodium caseinate (NaCas). We found that in this ratio, the CEO-loaded zein-NaCas (C/ZN) nanoparticles had smaller particle size, proper polydispersity index (PDI) and zeta potential as well as higher encapsulation efficiency. Then, the acquired C/ZN nanoparticles were incorporated into chitosan film at three levels (0.2%, 0.4% and 0.6%), reducing the water vapor permeability to 4.62 × 10-6 g·s-1·m-1·Pa. Also, the tensile strength and break elongation of chitosan films were increased, reaching 38.67 MPa and 1.56%, respectively. The infrared spectroscopy verified that the intermolecular hydrogen bonds exist between chitosan and C/ZN nanoparticles. The chitosan composite films showed a controlled-release property of CEO in 96 h. Finally, the chitosan composite films showed the improved antibacterial property by creating larger inhibition zones against Escherichia coli (3.29 mm) and Staphylococcus aureus (6.15 mm). In general, we improved the water resistance, light blocking, mechanical strength, controlled-release and antibacterial properties of chitosan film with C/ZN nanoparticles. The current edible antibacterial films have great potential on applications for food preservation and food delivery system.

Chitosan hydrochloride/carboxymethyl starch complex nanogels stabilized Pickering emulsions for oral delivery of ß-carotene: Protection effect and in vitro digestion study.

ß-Carotene was encapsulated in the Pickering emulsions stabilized by chitosan hydrochloride - carboxymethyl starch (CHC-CMS) nanogels. During ultraviolet radiation and storage, the retention of ß-carotene in Pickering emulsions was higher than that of other formulations, such as Tween 80 stabilized emulsions (TEs) and bulk oil. The Pickering emulsions were found to be stable during thermal treatment. Meanwhile, lipid oxidation was delayed in Pickering emulsions compared to TEs and bulk oil. The vitro digestion results suggested that the free fatty acids (FFA) released were below 30% for all Pickering emulsions, which indicated that a physical barrier was formed by CHC-CMS nanogels to restrain the lipid hydrolysis. The bioaccessibility of ß-carotene in Pickering emulsions was higher than that in bulk oil. This research helped establish a connection between the physicochemical properties of CHC-CMS stabilized Pickering emulsions with their applications in the protection effect and oral delivery of bioactive compounds.

Short- and medium-chain chlorinated paraffins in plastic animal feed packaging and factors affect their migration into animal feed.

Chlorinated paraffins (CPs) are used as plasticizers and flame retardants in plastics. Plastic packaging containing CPs is widely used for storage of animal feed, which can become contaminated by CPs that migrate into the feed. In the present study, 31 commercial animal feed packaging samples made of polypropylene (PP) or polyethylene (PE) were collected from animal feed manufacturers in China. The mean concentrations of short-chain chlorinated paraffins (SCCPs) in the PP and PE samples were 60.0 and 54.5 µg/g, respectively. The medium-chain chlorinated paraffin (MCCP) mean concentrations in the PP and PE samples were 62.7 and 9.23 µg/g, respectively. The carbon congener group profiles of SCCPs and MCCPs in the samples were different. The dominant SCCP and MCCP chlorine congener groups in all the samples were Cl6-7 and Cl6-8, respectively. Time and temperature influenced the migration of CPs from packaging into animal feed. As the time or temperature increased, the CP concentrations in the animal feed increased but the congener group profiles of the SCCPs and MCCPs in the animal feed did not change. To reduce contamination of animal feed by CPs, it is necessary to restrict the use of CPs in animal feed packaging.

[Study on the technics of adsorption and purification of baicalin by different macroporous resins].

OBJECTIVE: To ascertain the fittest technical parameters by studying the application of macroporous resins used to purify active components of baicalin. METHODS: To evaluate the ability of adsorption and re-adsorption of macroporous resins selected, the statical and dynamic adsorption-readsorption durations were also investigated to select the optimum macroporous resins, with the content of flavonoids as the standard. RESULTS: The optimum macroporous resins was HPD-100. In the adsorption cours, the ratio between the amount of medicinal materials and the volume of macroporous resins was 3.0 and there was no more absorbed when the ratio was 12.5; the optimum ethanol concentration was 50% in readsorption duration. CONCLUSION: HPD-100 is the optimum macroporous resin to purify bailcalin and enhance its refined rate.

Study on the effectiveness of ligand reversible shielding strategy in targeted delivery and tumor therapy.

We previously proved the superiority of the ligand reversible shielding strategy based on the pH-responsive self-assembly/disassembly of gold nanoparticles through computed tomography imaging in vivo. Herein, the practicality of this strategy in tumor therapy was investigated by a ligand reversible shielding system based on a temperature-responsive polymer. The ligand biotin, cisplatin-loaded chain poly(acrylic acid)-Pt, and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm)) were co-modified onto the surface of gold nanostars. In the blood circulation (37 °C), the ligand was shielded by the extension of P(NIPAAm-co-AAm), whose lower critical solution temperature (LCST) is approximately 39 °C. After the nanoparticles accumulate at the tumor site by the enhanced permeability and retention (EPR) effect, the heat generated from gold nanostars upon near-infrared light irradiation would trigger the contraction of P(NIPAAm-co-AAm), thus deshielding the ligand for enhanced tumor cellular uptake. Owing to the reversible extension-contraction transformation change of P(NIPAAm-co-AAm), the reversible shielding effect on the ligand could be accomplished even if the nanoparticles return to the blood circulation. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower), and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. This strategy showed significantly superior tumor inhibition (11% higher) than the irreversible system. All these results make clear that the ligand reversible shielding strategy is effective and offers important references for the design of nanomaterials for improving tumor accumulation. STATEMENT OF SIGNIFICANCE: Herein, the practicality of the ligand reversible shielding strategy in tumor therapy was investigated. The ligand biotin, cisplatin loaded chain poly(acrylic acid)-Pt and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm) which LCST is about 39 °C) were co-modified onto the surface of gold nanostars. This well-designed NPs could shield target ligand in blood circulation (37 °C) and deshield it at tumor site (40-41 °C) reversibly. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower) and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. Significantly, the strategy showed superior tumor inhibition than the irreversible system (11% higher).

Fabrication of chitosan hydrochloride and carboxymethyl starch complex nanogels as potential delivery vehicles for curcumin.

The purpose of this research was to prepare nanogels by covalent cross-linking carboxymethyl starch (CMS) and chitosan hydrochloride (CHC) as novel delivery systems for curcumin. The spherical structure of CHC-CMS nanogels was verified by transmission electron microscopy. Fourier transform infrared spectroscopy confirmed that the amide linkage was formed between CHC and CMS. X-ray diffraction data exhibited that the crystalline structure of CHC was destroyed after covalent cross-linking with CMS, which further confirmed that the CHC-CMS nanogels were formed. Furthermore, the nanogels behaved as viscoelastic solids over the entire frequency range. Meanwhile, the nanogels showed excellent pH-sensitivity and high encapsulation efficiency of curcumin (89.49%-94.01%). Compared to free curcumin, curcumin encapsulated in nanogels displayed sustained release profile in simulated gastrointestinal conditions. These results suggested that the nanogels had been successfully fabricated and could be used as ideal carriers for curcumin and other bioactive compounds in functional foods.

Intermolecular interactions of polysaccharides in membrane fouling during microfiltration.

Membrane technology has been widely employed for seawater desalination, water and wastewater reclamation, while membrane fouling still remains as a major challenge. The polysaccharides in extracellular polymeric substances (EPS) have been recognized as an important foulant that causes serious membrane fouling, while the detailed structure of polysaccharides and the intermolecular interactions between them have not been adequately disclosed. In this study, two different polysaccharides and their mixtures were used to study the intermolecular cross-linking of polysaccharides as well as its effects on membrane fouling. Results demonstrated that the fouling propensities of distinct polysaccharides were completely different, which was attributed to the different intermolecular interactions lying in polysaccharides. The cross-linking among molecules of polysaccharide, regardless of the homogeneity, was found to form complex networks and determine the effective dimension of polysaccharides. Depending on the effective dimension of foulants, pore blocking and cake layer occurred subsequently during filtration processes. In light of this, it potentially gives new insights into the fouling behaviours by combining the structure-function knowledge of polysaccharides with their fouling propensity. In addition, transparent exopolymeric particles (TEP) measurement was found to provide an intuitionistic evaluation of the complex networks formed from polysaccharides, so that may act as a good indicator of fouling during membrane filtration.

A novel self-assembled nanoparticle platform based on pectin-eight-arm polyethylene glycol-drug conjugates for co-delivery of anticancer drugs.

The application of non-toxic carriers to increase drug loading, multi-drug delivery, and extremely small size of nano-drugs to construct a tremendous transmission system is the goal for all researchers to be pursued. The proposal of natural pectin nano-platform for delivery of multiple drugs is critical for biomedical research, especially a particle size of below 100nm with high yield. Here we design a new core-shell structure pectin-eight-arm polyethylene glycol-ursolic acid/hydrooxycampothecin nanoparticle (Pec-8PUH NPs) through a special self-assembly method for stabilizing and dispersing particles, improving water-solubility, and achieving drug controlled release. The obtained Pec-8PUH NPs possessed appropriate size (~91nm), drug-loaded efficiency and encapsulation efficiency through the regulation of eight-arm polyethylene glycol. In addition, Pec-8PUH NPs could enhance cell cytotoxicity, shorten blood retention time (7.3-fold UA, 7.2-fold HCPT) and more effective cellular uptake than free drugs, which exhibited an obvious synergistic effect of UA and HCPT by the co-delivery. 4T1 tumor-bearing mice also showed a higher survival rate than free UA and free HCPT. The result further shows that this novel drug delivery system has a promising potential for anti-cancer combination therapy.

Near-infrared rechargeable "optical battery" implant for irradiation-free photodynamic therapy.

As a minimal or noninvasive therapeutic method for tumors, photodynamic therapy (PDT) induced by the external laser irradiations has attracted great attentions. However, the UV-visible responsive property with low tissue penetration and photothermal effect from the prolonged irradiation impedes their further applications. Herein, a near-infrared (NIR) rechargeable "optical battery" for irradiation-free PDT is fabricated by embedding upconversion materials, persistent luminescence materials, photosensitizer into biocompatible polydimethylsiloxane. After 5 s quickly charged by 980-nm NIR laser, the PDT "optical battery" can generate green persistent luminescence and produce cytotoxic singlet oxygen for continuous irradiation-free PDT (∼30 min) without external irradiation. Due to deep tissue penetration and discontinuous short exposure of NIR light charging source, the "optical battery" can still be charged to continuously generate singlet oxygen in deep tissue (∼4 mm) with low photothermal effect. The PDT implant can be easily optimized in size and shape aiming at different nidus sites and achieved different functions by adding other functional components (e.g. CaO2 for oxygen envolving to overcome hypoxia tumor). The effective tumor proliferation inhibiting capability of this NIR rechargeable "optical battery" may give rise to next generation of intelligent stimuli-responsive nanomedicine and noninvasive photo bio-stimulation research for future clinical applications.