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Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased production of ROS may disrupt cellular homeostasis, giving rise to oxidative stress and a series of diseases. Utilizing these cell‐generated species as triggers for selective tuning polymer structures and properties represents a promising methodology for disease diagnosis and treatment. Recently, significant progress has been made in fabricating biomaterials including nanoparticles and macroscopic networks to interact with this dynamic physiological condition. These ROS‐responsive platforms have shown potential in a range of biomedical applications, such as cancer targeted drug delivery systems, cell therapy platforms for inflammation related disease, and so on.

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A series of pH-and temperature-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) (P(NIPAM-co-AAD)) copolymers and hydrogels were prepared. The lower critical solution temperatures (LCSTs) of the copolymers exhibited a dependence on both pH and the hydrophobicity of the AAD unit. The influence of pH and temperature on the equilibrium swelling ratio of the hydrogels was investigated. The hydrogels displayed a unique thermo-induced swelling-deswelling transition that can be self-regulated to occur at above or below the physiological temperature in response to the environmental pH. Scanning electron microscopic (SEM) analysis revealed porous sponge-like microstructures of the hydrogels. Insulin was loaded into the hydrogels as a model protein, and the in vitro release profiles indicated that the loaded protein could be protected within the hydrogels in an acidic environment and selectively released in neutral medium. MTT assay proved that both the copolymers and hydrogels are nontoxic. After oral administration of the insulin-loaded hydrogels to streptozotocin-induced diabetic rats at 60 IU per kg, the fasting plasma glucose level was reduced continuously to 72.1% within 6 h. The bioavailability of hydrogel-encapsulated insulin via the oral administration to healthy rabbits reached 5.24%, which is much higher than that of pure insulin solution given orally. These results showed that the smart copolymers and hydrogels may hold great promise for pH-triggered drug delivery systems.

Rapid gelation and on‐demand dissolution are key characteristics governing the effectiveness of clinic hydrogel wound dressings. Here, an injectable self‐healing hydrogel with rapid gelation and cysteine‐specific on‐demand dissolution is designed to be used as wound dressings. The hydrogel is prepared based on the formation of tandem dynamic covalent bonds comprised of CC double bonds produced through the catalysis‐free Knoevenagel condensation reaction and boronate ester linkages. The prepared hydrogel displays excellent injectability and self‐healing ability, showing rapid cysteine‐triggered on‐demand dissolution owing to the formation of the thiazolidino boronate complex. When used as dressings for healing full‐thickness wounds, the hydrogel shows favorable biocompatibility, achieves rapid wound closure in seconds, and fast on‐demand dissolution for dressing changes. These data highlight the utility of the designed tandem dynamic covalent bonds‐based hydrogel dressings for promising wound healing applications.

Conventional small-molecule antibiotics are facing a significant challenge of the rapidly developed drug resistance of pathogens. In contrast, antimicrobial peptides (AMPs), an important component for innate host defenses, are now under intensive investigation as a promising antimicrobial agent for combating drug resistant pathogens. Most AMPs can effectively kill a broad spectrum of pathogens via physical disruption of microbial cellular membranes, which is identified to be difficult to develop resistance. However, the clinical applications of AMPs are still greatly limited by several inherent impediments, such as high cost of production, potential hemolysis or toxicity, and liability to proteinase degradation. Recently, cationic poly(α-amino acid)s with structures mimicking the AMPs are found to have excellent antimicrobial activity. These polymers, termed "antimicrobial poly(α-amino acid)s (APAAs)," have some advantages over AMPs, such as easy production and modification, prolonged antimicrobial activity, low cytotoxicity, and enhanced stability to protease degradation. Here, a brief introduction of mechanisms and affecting factors of microbial killing by AMPs is first presented, followed by a systematic illustration of recent advances in design and preparation of biomimetic APAAs and a perspective in this field.

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Combining intracellularly active proteins with chemotherapeutics represents a promising strategy for synergistic cancer therapy. However, the lack of nanocarrier systems for delivery into cancer cells and controlled intracellular release of both physicochemically very distinct cargos significantly impedes the biomedical translation of this combination strategy in cancer therapy. Here, a well‐designed triblock copolymer, mPEG‐b‐PGCA‐b‐PGTA, is reported for application in a multistage cooperative drug delivery nanoplatform that accomplishes effective intracellular co‐delivery of hydrophilic ribonuclease A (RNase A) and hydrophobic doxorubicin (DOX). RNase A bioreversibly modified with phenylboronic acid groups via a ROS‐cleavable carbamate linker is incorporated into the triblock copolymer nanoparticles with high efficiency through a pH‐reversible phenylboronic acid–catechol linkage. The reversible covalent conjugations between RNase A and the triblock copolymer endow the nanoparticles with high stability under normal physiological conditions. Upon cellular internalization, the cooperative release of DOX and RNase A from the triblock copolymer nanoparticles is triggered at multiple stages by endosomal acidic environment and subsequent DOX‐enhanced intracellular ROS environment. This leads to enhanced synergistic anticancer effects as demonstrated both in vitro and in vivo. Given the versatility of dynamic covalent conjugations, this work provides a universal and stable platform for intracellular co‐delivery of various combinations of proteins and chemotherapeutics.