Cationic Single-Unit Monomer Insertion (cSUMI): From Discrete Oligomers to the α-/ω-End and In-Chain Sequence-Regulated Polymers.

Single-unit monomer insertion (SUMI) has become an important strategy for the synthesis of sequence-controlled vinyl polymers due to its strong versatility and high efficiency. However, all reported SUMI processes are based on a free-radical mechanism, resulting in a limited number of monomer types being applicable to SUMI or a limited number of sequences of structural units that SUMI can synthesize. Herein, we developed a novel SUMI based on a cationic mechanism (cSUMI), which operates through a degenerative (similar to radical SUMI) but cationic chain transfer process. By optimizing the chain transfer agent (CTA) and monomer pairs, a high-efficiency cSUMI was achieved for vinyl ether and styrene monomers. Based on this reaction, a range of discrete oligomers containing vinyl ether and styrene moieties, and even α-/ω-end and in-chain sequence-regulated polymers were synthesized, most of which cannot be achieved by radical SUMI. In addition, we explored the application of these sequence-regulated polymers in the preparation of miktoarm star polymers, delivery of photosensitizers, and solubilization of fluorescence probes. The development of SUMI with a new mechanism will certainly broaden the scope of structures and sequences in precise vinyl-based polymers.

Label-Free Quantification of Digital Nanorods Assembled from Discrete Oligourethane Amphiphiles.

Polymeric nanoparticles (NPs) have been extensively designed for theranostic agent delivery. Previous methods for tracking their biological behavior and assessing theranostic efficacy heavily rely on fluorescence or isotope labeling. However, these labeling techniques may alter the physicochemical properties of the labeled NPs, leading to inaccurate biodistribution information. Therefore, it is highly desirable to develop label-free techniques for accurately assessing the biological fate of polymeric NPs. Here, we create discrete oligourethane amphiphiles (DOAs) with methoxy (OMe), hydroxyl (OH), and maleimide (MI) moieties at the dendritic oligo(ethylene glycol) (dOEG) ends. We obtained four types of digital nanorods (NRs) with distinct surface functional groups through self-assembly of a single DOA (OMe and OH NRs) or coassembly of two DOAs (OMe-MI and OH-MI NRs). These unique NRs can be directly quantified in a label-free manner by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Specifically, OMe-MI NRs exhibited the best blood circulation, and OH-MI showed the highest area under the curve (AUC) value after intravenous injection. Biodistribution studies demonstrated that MI-containing NRs generally had lower accumulation in the liver and spleen compared to that of MI-free NRs, except for the comparison between OMe and OMe-MI NRs in the liver. Proteomics studies unveiled the formation of distinct protein coronas that may greatly affect the biological behavior of NRs. This study not only provides a label-free technique for quantifying the pharmacokinetics and biodistribution of polymeric NRs but also highlights the significant impact of surface functional groups on the biological fate of polymeric NPs.

Overcoming the Dilemma of Permeability and Stability of Polymersomes through Traceless Cross-Linking.

In nature, cells are highly compartmentalized into many organelles that are well separated from the rest of the cellular space by unique membrane structures, which are of crucial importance to allow cells to perform various physiological functions in such a small and crowded space. Learning from the ubiquitous membrane structures of cells and organelles has continuously inspired the development of artificial self-assembled nanostructures, with lipid vesicles (liposomes) and polymer vesicles (polymersomes) being the most representative examples. Similar to the membrane-bound structures of cells and organelles, both liposomes and polymersomes contain an aqueous interior enclosed by a bilayer membrane. Therefore, liposomes and polymersomes have been extensively investigated to mimic the fundamental structures and functions of living cells. For example, liposomes and polymersomes have been successfully engineered as nanocarriers, smart nanoreactors, artificial organelles, and so on. Notably, living cells can exchange both energy and materials with surrounding environments, benefiting from the selective permeability of lipid membranes. The permselectivity of cell membranes is thus an essential attribute of living organisms. Compared to liposomes, polymersomes have increased structural stability but low membrane permeability. Indeed, polymersomes are almost impermeable to small molecules, ions, and even water molecules. To improve the permeability of polymersomes, much effort has been devoted to the incorporation of channel proteins, the coassembly of oppositely charged block copolymers (BCPs), the development of stimuli-responsive BCPs, and so on. Despite great achievements, these approaches generally lead to decreased stability of polymersomes and, sometimes, polymersome disintegration. In this Account, we discuss our recent efforts to reconcile the stability and permeability of polymersomes via a traceless cross-linking approach. Although cross-linking reactions within bilayer membranes generally lead to decreased permeability, the traceless cross-linking approach can concurrently improve the stability and permeability of polymersomes. Specifically, stimuli-responsive polymersomes undergo either covalent cross-linking or noncovalent cross-linking reactions under specific stimuli to increase bilayer stability, while the cross-linking processes can concurrently permeabilize polymersome bilayers through cross-linking-driven hydrophobic-to-hydrophilic transitions. Notably, unlike conventional cross-linking processes requiring additional cross-linkers, the traceless cross-linking process does not involve extra cross-linking agents but takes full advantage of the in situ generated active moieties. By taking advantage of the simultaneous modulation of the stability and permeability of polymersomes via traceless cross-linking, these polymersomes can be further engineered as smart nanocarriers and nanoreactors. The robustness and generality of this approach have been validated by both extracellular and intracellular stimuli such as light irradiation, glutathione, and hydrogen peroxide. Moreover, many functional groups such as fluorescent dyes and contrast agents can be integrated into this versatile platform as well, enabling the construction of theranostic nanovectors capable of responding to pathological microenvironments. This Account provides a new approach to regulating the permeability of polymersomes while maintaining their structural stability.

Cytotoxic steroidal saponins from the rhizomes of Paris fargesii var. Petiolata.

Phytochemical investigation on the rhizomes of Paris fargesii var. petiolata (Baker ex C. H. Wright) Wang et Tang led to the isolation of five previously undescribed steroidal saponins, parpetiosides A-E (1-5), and six known analogs (6-11). Their structures were established by extensive spectroscopic data analysis and chemical methods. Compound 5 was a rare steroidal saponin with disaccharide moiety linked at C-26 of dehydrokryptogenin that was hardly seen in the genus Paris. The cytotoxicities of the isolated compounds against three human cancer cell lines (U87, HepG2 and SGC-7901) were evaluated, and compound 1 displayed certain inhibitory effect with IC50 values of 8.02 ± 0.45, 8.24 ± 0.57 and 6.20 ± 0.79 µM, respectively. Moreover, the preliminary mechanism of 1 inhibiting the proliferation of the three cancer cell lines might be related to cell cycle distribution and the induction of S phase arrest.

Local delivery of gaseous signaling molecules for orthopedic disease therapy.

Over the past decade, a proliferation of research has used nanoparticles to deliver gaseous signaling molecules for medical purposes. The discovery and revelation of the role of gaseous signaling molecules have been accompanied by nanoparticle therapies for their local delivery. While most of them have been applied in oncology, recent advances have demonstrated their considerable potential in diagnosing and treating orthopedic diseases. Three of the currently recognized gaseous signaling molecules, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), are highlighted in this review along with their distinctive biological functions and roles in orthopedic diseases. Moreover, this review summarizes the progress in therapeutic development over the past ten years with a deeper discussion of unresolved issues and potential clinical applications.

Reforestation substantially changed the soil antibiotic resistome and its relationships with metal resistance genes, mobile genetic elements, and pathogens.

Revealing the effects of reforestation on soil antibiotic resistome is essential for assessing ecosystem health, yet related studies remain scarce. Here, to determine the responses of the soil antibiotic resistome to reforestation, 30 pairs of cropland and forest soil samples were collected from southwestern China, a region with high environmental heterogeneity. All the forests had been derived from croplands more than one decade ago. The diversity and abundance of soil antibiotic resistance genes (ARGs), metal resistance genes (MRGs), mobile genetic elements (MGEs), and pathogens were determined by metagenomic sequencing and real-time PCR. The results showed that reforestation significantly increased soil microbial abundance and the contents of Cu, total carbon, total nitrogen, total organic carbon, and ammonium nitrogen. Nevertheless, it decreased the contents of soil Zn, Ba, nitrate nitrogen, and available phosphorus. The main soil ARGs identified in this region were vancomycin, multidrug, and bacitracin resistance genes. Reforestation significantly increased the soil ARG abundance by 62.58%, while it decreased the ARG richness by 16.50%. Reforestation exerted no significant effects on the abundance of heavy metal resistance genes and pathogens, but it doubled the abundance of MGEs. Additionally, reforestation substantially decreased the co-occurrence frequencies of ARGs with MRGs and pathogens. In contrast, the correlation between ARGs and MGEs was greatly enhanced by reforestation. Similarly, the correlations between soil ARG abundance and environmental factors were also strengthened by reforestation. These findings suggest that reforestation can substantially affect the soil antibiotic resistome and exerts overall positive effects on soil health by decreasing ARG richness, providing critical information for assessing the effects of "grain for green" project on soil health.

Effects of taurine on rumen fermentation, nutrient digestion, rumen bacterial community and metabolomics and nitrogen metabolism in beef steers.

BACKGROUND: The objectives of this study were to investigate the effects of taurine on rumen fermentation, rumen bacterial community and metabolomics, nitrogen metabolism and plasma biochemical parameters in beef steers. Six castrated Simmental steers (liveweight 402 ± 34 kg) and three levels of taurine (0, 20, 40 g d-1 ) were assigned in a replicated 3 × 3 Latin square design. Each experimental period included 15 days for adaptation and 5 days for sampling. RESULTS: Supplementing taurine did not affect the ruminal pH or concentrations of ammonia nitrogen and volatile fatty acids (P > 0.10), but linearly increased the ruminal concentrations of taurine (P < 0.001) and microbial crude protein (P = 0.041). Supplementing taurine linearly increased the neutral detergent fiber digestibility (P = 0.018), and tended to linearly increase dry matter digestibility (P = 0.095), tended to increase the fecal nitrogen excretion (P = 0.065) and increased the urinary taurine excretion (P < 0.001). Supplementing taurine quadratically increased the plasma concentration of triglycerides (P = 0.017), tended to linearly decrease growth hormone (P = 0.074), but did not affect other plasma parameters (P > 0.10). Supplementing taurine modified the rumen bacterial community and increased the ruminal concentration of taurine metabolite 2-hydroxyethoxysulfonic acid (P < 0.001). CONCLUSION: It was concluded that taurine improved ruminal microbial crude protein synthesis and increased fiber digestibility through modifying rumen bacterial community. It is necessary to clarify the ruminal hydrolysis of taurine in steers. © 2023 Society of Chemical Industry.

Research on accuracy of material identification based on photon counting spectral CT.

BACKGROUND: Photon counting spectral CT is a significant direction in the development of CT technology and material identification is an important application of spectral CT. However, spectrum estimation in photon counting spectral CT is highly complex and may affect quantification accuracy of material identification. OBJECTIVE: To address the problem of energy spectrum estimation in photon-counting spectral CT, this study investigates empirical material decomposition algorithms to achieve accurate quantitative decomposition of the effective atomic number. METHODS: The spectrum is first calibrated using the empirical dual-energy calibration (EDEC) method and the effective atomic number is then quantitatively estimated based on the EDEC method. The accuracy of estimating the effective atomic number of materials under different calibration conditions is investigated by designing different calibration phantoms, and accurate quantitation is achieved using suitable calibration settings. Last, the validity of this method is verified through simulations and experimental studies. RESULTS: The results demonstrate that the error in estimating the effective atomic number is reduced to within 4% for low and medium Z materials, thereby enabling accurate material identification. CONCLUSION: The empirical dual-energy correction method can solve the problem of energy spectrum estimation in photon counting spectral CT. Accurate effective atomic number estimation can be achieved with suitable calibration.

A Single-Component Dual Donor Enables Ultrasound-Triggered Co-release of Carbon Monoxide and Hydrogen Sulfide.

The development of dual gasotransmitter donors can not only provide robust tools to investigate their subtle interplay under pathophysiological conditions but also optimize therapeutic efficacy. While conventional strategies are heavily dependent on multicomponent donors, we herein report an ultrasound-responsive water-soluble copolymer (PSHF) capable of releasing carbon monoxide (CO) and hydrogen sulfide (H2 S) based on single-component sulfur-substituted 3-hydroxyflavone (SHF) derivatives. Interestingly, sulfur substitution can not only greatly improve the ultrasound sensitivity but also enable the co-release of CO/H2 S under mild ultrasound irradiation. The co-release of CO/H2 S gasotransmitters exerts a bactericidal effect against Staphylococcus aureus and demonstrates anti-inflammatory activity in lipopolysaccharide-challenged macrophages. Moreover, the excellent tissue penetration of ultrasound irradiation enables the local release of CO/H2 S in the joints of septic arthritis rats, exhibiting superior therapeutic efficacy without the need for any antibiotics.

Dendritic Quaternary-Encoded Oligourethanes for Data Encryption.

The use of sequence-defined digital polymers for data storage and encryption has received increasing attention due to their precision structures similar to natural biomacromolecules (e.g., DNA) but increased stability. However, the rapid development of sequencing techniques raises the concern of information leakage. Herein, dendritic quaternary-encoded oligourethanes bearing a photoresponsive trigger, self-immolative backbones, and a mass spectrometry tag of PEG dendron have been developed for data encryption. Although the sequence information in linear analogs can be readily deciphered by mass spectrometry, sequencing of dendritic oligourethanes cannot be achieved by either primary MS or tandem MS/MS owing to the unique spatial conformation. Intriguingly, the fragmentation pathways of a quaternary dendrimer under MS/MS conditions can be converted to 2772-bit 2D matrices with ≈1.98×1087 permutations, serving as high-strength encryption keys for highly reliable data encryption.

Overcoming the Oxygen Dilemma in Photoredox Catalysis: Near-Infrared (NIR) Light-Triggered Peroxynitrite Generation for Antibacterial Applications.

The peroxynitrite anion (ONOO- ) is closely associated with many diseases and the creation of ONOO- donors is an essential means of understanding its pathophysiological functions. However, it is challenging to develop ONOO- donors due to the difficulties in simultaneously producing highly reactive and short-lived nitric oxide (NO) and superoxide anion (O2 ⋅- ). Here, we report a novel strategy for constructing ONOO- donors by combining near-infrared (NIR)-mediated type I photosensitization and photoredox catalysis. The key design using a Nile blue analogue that can serve as both a type I photosensitizer and a metal-free photocatalyst. Intriguingly, the formation of O2 ⋅- via type I photosensitization avoids oxygen interference and instead activates nitrobenzofurazan-based NO donors via oxygen-tolerant NIR photoredox catalysis. The simultaneous release of O2 ⋅- and NO leads to ONOO- release, showing both antibacterial and antibiofilm activities.

Controlled Self-Assembly of Discrete Amphiphilic Oligourethanes with a Cascade Self-Immolative Motif.

Discrete polymers offer an excellent platform for comprehending the interplay between precise chain structures, distinctive self-assembly behavior, and functional applications, whereas the development of discrete polymers with self-immolative properties remains scarce. Here, we modularly synthesize a library of discrete self-immolative oligourethanes containing N-naphthylcarbamate or N-(3-fluorophenyl)carbamate repeating units via iterative stepwise growth. These oligourethanes undergo not only cascade 1,6-elimination depolymerizations via photo-mediated removal of o-nitrobenzyl carbamate triggers but also selective cleavage of benzyl-O linkages under MS/MS conditions even without UV light irradiation. In aqueous media, these discrete oligourethanes self-assemble into different morphologies such as flat nanosheets, nanofibers, and nanoribbons, depending on the chain lengths and backbone compositions, and further morphological transitions are observed upon thermal annealing.

Spontaneous Resolution of Racemic Cage-Catenanes via Diastereomeric Enrichment at the Molecular Level and Subsequent Narcissistic Self-Sorting at the Supramolecular Level.

The spontaneous resolution of racemates, from natural compounds to artificial structures, has long been pursued to shed light on the origin of homochirality in life. Even though diverse synthetic systems have been elegantly devised to elaborate the underlying principles of spontaneous symmetry breaking, their complexity is still unparalleled to the natural masterpieces including DNA helix and proteins, which convey remarkable coalescence at both molecular and supramolecular levels. Here, we report on the spontaneous resolution of a pair of homochiral entities from a racemic mixture of a triply interlocked cage-catenane comprising 720 possible stereoisomers. This cage-catenane comprises six methyldithiane ring-containing linkers (denoted rac-2). As each methyldithiane ring has two chiral centers, it exhibits four possible diastereomers. These otherwise equimolar diastereomers are preferentially differentiated with the equatorial conformers over their axial analogues, leading to the dominant formation of (S, R)-2 and (R, S)-2, i.e., diastereomeric enrichment at the molecular level. This diastereomeric enrichment is unbiasedly transferred from precursor rac-2 to cage-catenane rac-4, from which a pair of homochirals (S, R)6-4 and (R, S)6-4 is narcissistically self-sorted upon crystallization. This powerful symmetry breaking is attributed to a supramolecular synergy of directional π-π stacking with the multivalency of erstwhile weak S···S contacts (with an unusual distance of 3.09 Å) that are cooperatively arranged in a helical fashion. This work highlights the attainability of complex homochiral entities by resorting to coalesced covalent and noncovalent contributions and therefore provides additional clues to the symmetry breaking of sophisticated yet well-defined architectures.

The earliest hylobatid from the Late Miocene of China.

Yuanmoupithecus xiaoyuan, a small catarrhine from the Late Miocene of Yunnan in southern China, was initially suggested to be related to Miocene proconsuloids or dendropithecoids from East Africa, but subsequent reports indicated that it might be more closely related to hylobatids. Here, detailed comparisons of the material, including seven newly discovered teeth and a partial lower face of a juvenile individual, provide crucial evidence to help establish its phylogenetic relationships. Yuanmoupithecus exhibits a suite of synapomorphies that support a close phylogenetic relationship with extant hylobatids. Furthermore, based on the retention of several primitive features of the dentition, Yuanmoupithecus can be shown to be the sister taxon of crown hylobatids. The contention that Kapi ramnagarensis from the Middle Miocene of India might represent an earlier species of hylobatid is not supported here. Instead, Kapi is inferred to be a specialized pliopithecoid more closely related to Krishnapithecus krishnaii from the Late Miocene of India. Currently then, Yuanmoupithecus represents the earliest known definitively identified hylobatid and the only member of the clade predating the Pleistocene. It extends the fossil record of hylobatids back to 7-8 Ma and fills a critical gap in the evolutionary history of hominoids that has up until now remained elusive. Even so, molecular estimates of a divergence date of hylobatids from other hominoids at about 17-22 Ma signifies that there is still a substantial gap in the fossil record of more than 10 million years that needs to be filled in order to document the biogeographic origins and early evolution of hylobatids.

Ultrasound-Mediated Release of Gaseous Signaling Molecules for Biomedical Applications.

Although nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2 S) have been considered as notorious gas pollutants for decades, they are considered as endogenous gaseous signaling molecules (GSMs), which have been widely recognized for their important signaling functions and prominent medical applications in human physiology. To achieve local delivery of GSMs to optimize therapeutic efficacy and reduce systemic side effects, stimuli-responsive nanocarriers have been successfully developed. Among them, ultrasound is considered as an attractive theranostic modality that can be used to track drug carriers, trigger drug release, and improve drug deposition, etc. In this minireview, recent achievements in designing ultrasound-responsive nanocarriers for the controlled delivery of GSMs and their biomedical applications are summarized. This emerging research direction enables the controlled delivery of GSMs to deep tissues, and the combination of ultrasound imaging techniques offers many possibilities for the fabrication of new theranostic platforms.

Orchestrating Nitric Oxide and Carbon Monoxide Signaling Molecules for Synergistic Treatment of MRSA Infections.

The local delivery of gaseous signaling molecules (GSMs) has shown promising therapeutic potential. However, although GSMs have a subtle interplay in physiological and pathological conditions, the co-delivery of different GSMs for therapeutic purposes remains unexplored. Herein, we covalently graft a nitric oxide (NO)-releasing N-nitrosamine moiety onto the carbon monoxide (CO)-releasing 3-hydroxyflavone (3-HF) antenna, resulting in the first NO/CO-releasing donor. Under visible light irradiation, photo-mediated co-release of NO and CO reveals a superior antimicrobial effect toward Gram-positive bacteria with a combination index of 0.053. The synergy of NO and CO hyperpolarizes and permeabilizes bacterial membranes, which, however, shows negligible hemolysis and no evident toxicity toward normal mammalian cells. Moreover, the co-release of NO and CO can efficiently treat MRSA infection in a murine skin wound model, showing a better therapeutic capacity than vancomycin.

Nitric-Oxide-Releasing aza-BODIPY: A New Near-Infrared J-Aggregate with Multiple Antibacterial Modalities.

The development of near-infrared (NIR) J-aggregates has received increasing attention due to their broad applications. Here, we report the nitrosation of an amine-containing aza-BODIPY precursor (BDP-NH2 ), affording the first nitric oxide (NO)-releasing NIR J-aggregate (BDP-NO). The introduction of N-nitrosamine moieties efficiently inhibits the aromatic interactions of BDP-NH2 , which instead promotes the formation of J-aggregates within micellar nanoparticles with a remarkable bathochromic shift of ≈109 nm to the NIR window (820 nm). Interestingly, the NO release and photothermal conversion efficiency (PTCE) can be delicately tuned by the loading contents of BDP-NO within micellar nanoparticles, thereby enabling multiple antibacterial modalities by exploring either NO release, photothermal therapy (PTT), or both. We demonstrate the combination of NO and PTT can elevate antibacterial activity while attenuating PTT-associated inflammation for the in vivo treatment of MRSA infection.

Oxygen-Tolerant Photoredox Catalysis Triggers Nitric Oxide Release for Antibacterial Applications.

Photoredox catalysis has emerged as a robust tool for chemical synthesis. However, it remains challenging to implement photoredox catalysis under physiological conditions due to the complex microenvironment and the quenching of photocatalyst by biologically relevant molecules such as oxygen. Here, we report that UV-absorbing N,N'-dinitroso-1,4-phenylenediamine derivatives can be selectively activated by fac-Ir(ppy)3 photocatalyst within micellar nanoparticles under visible light irradiation (e.g., 500 nm) through photoredox catalysis in aerated aqueous solutions to form quinonediimine (QDI) residues with concomitant release of NO. Notably, the formation of QDI derivatives can actively scavenge the reactive oxygen species generated by fac-Ir(ppy)3 , thus avoiding oxygen quenching of the photocatalyst. Further, we exemplify that the oxygen-tolerant photoredox catalysis-mediated NO release can not only kill planktonic bacteria in vitro but also efficiently treat MRSA infections in vivo.

Fluorinated Copolypeptide-Stabilized Microbubbles with Maleimide-Decorated Surfaces as Long-Term Ultrasound Contrast Agents.

Gas-filled microbubbles (MBs) have been clinically used as ultrasound (US) contrast agents for disease diagnosis and treatment. However, it remains a great challenge to resolve the dilemma of stability and contrast enhancement of MBs. Herein, amphiphilic copolypeptides bearing fluorinated blocks are synthesized to stabilize perfluorocarbon (PFC)-filled MBs, exhibiting unique stability under both long-term storage and US imaging conditions. The fluorinated inner layer reduces the internal Laplace pressure and greatly improves the stability of MBs, which can be further reinforced by crosslinking of the dipropargyl-containing middle blocks. To overcome the suppressed nonlinear oscillation of polymer shells, maleimide groups are introduced onto the surface of MBs, enabling in situ reaction with plasma proteins to enhance second harmonic signals without compromising the stability of MBs, conferring better US imaging performance than that of SonoVueTM MBs.

Coordinating External and Built-In Triggers for Tunable Degradation of Polymeric Nanoparticles via Cycle Amplification.

The selective activation of nanovectors in pathological tissues is of crucial importance to achieve optimized therapeutic outcomes. However, conventional stimuli-responsive nanovectors lack sufficient sensitivity because of the slight difference between pathological and normal tissues. To this end, the development of nanovectors capable of responding to weak pathological stimuli is of increasing interest. Herein, we report the fabrication of amphiphilic polyurethane nanoparticles containing both external and built-in triggers. The activation of external triggers leads to the liberation of highly reactive primary amines, which subsequently activates the built-in triggers with the release of more primary amines in a positive feedback manner, thereby triggering the degradation of micellar nanoparticles in a cycle amplification model. The generality and versatility of the cycle amplification concept have been successfully verified using three different triggers including reductive milieu, light irradiation, and esterase. We demonstrate that these stimuli-responsive nanoparticles show self-propagating degradation performance even in the presence of trace amounts of external stimuli. Moreover, we confirm that the esterase-responsive nanoparticles can discriminate cancer cells from normal ones by amplifying the esterase stimulus that is overexpressed in cancer cells, thereby enabling the selective release of encapsulated payloads and killing cancer cells. This work presents a robust strategy to fabricate stimuli-responsive nanocarriers with highly sensitive property toward external stimuli, showing promising applications in cancer therapy with minimized side effects.