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Trends in the development of modern medicine necessitate the efficient delivery of therapeutics to achieve the desired treatment outcomes through precise spatiotemporal accumulation of therapeutics at the disease site. Bioresponsive nanomedicine is a promising platform for this purpose. Dynamic covalent bonds (DCBs) have attracted much attention in studies of the fabrication of bioresponsive nanomedicines with an abundance of combinations of therapeutic modules and carrier function units. DCB-based nanomedicines could be designed to maintain biological friendly synthesis and site-specific release for optimal therapeutic effects, allowing the complex to retain an integrated structure before accumulating at the disease site, but disassembling into individual active components without compromising function in the targeted organs or tissues. In this review, we focus on responsive nanomedicines containing dynamic chemical bonds that can be cleaved by various specific stimuli, enabling achievement of targeted drug release for optimal therapy in various diseases.

Purpose Some chemotherapeutics have been shown to induce both the release of damage-associated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood-brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain. Methods A new oligonucleotide nanoformulation (Au@PP)/poly(I:C)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(I:C)). Intracranial GL261 tumor-bearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(I:C) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses. Results Au@PP/poly(I:C) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(I:C) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(I:C) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(I:C) plus TMZ group. Conclusion This study demonstrates that intranasal administration of Au@PP/poly(I:C) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.

Spinal cord injury (SCI) can disrupt neural circuitry and connectivity, leading to neurological and motor disabilities. Functional recovery relies on neuroplasticity and injured axon regeneration to rebuild connections and circuits. Current drugs with potential neuropharmacological effects are rapidly metabolized after systemic administration, reducing their pharmaceutical activity. Thus, efficient treatment of SCI remains a challenge. In this study, we designed click chemistry-conjugated protein-drug micelles (FPAaF) by the conjugation of insoluble ferrostatin-1 (Fer-1) and dibenzocyclooctyne (DBCO) modules to amphiphilic polymers, followed by click chemistry assembly with pH-responsive azido linker-modified acidic fibroblast growth factor (aFGF). SCI rats receiving systemic administration of FPAaF showed improved blood circulation and enhanced accumulation in the spinal cord. In vitro and in vivo studies showed the anti-ferroptotic and anti-inflammatory effects of FPAaF micelles. Moreover, significant improvements in neural and motor recovery were achieved upon the release of Fer-1 and aFGF in the acidic SCI microenvironment, which resulted in anti-ferroptotic and anti-inflammatory activities. This study shows that Fer-1 and aFGF conjugated micelles may exert their synergistic pharmacological effects on SCIs, suggesting that this is a promising strategy for the treatment of as-yet-incurable diseases.

Summary The stability of protein structures and biological functions at normal temperature is closely linked with the universal aqueous environment of organisms. Preserving bioactivities of proteins in hyperthermia water would expand their functional capabilities beyond those in native environments. However, only a limited number of proteins derived from hyperthermophiles are thermostable at elevated temperatures. Triggered by this, here we describe a general method to stabilize mesophilic proteins in hyperthermia water. The mesophilic proteins, protected by amphiphilic polymers with multiple binding sites, maintain their secondary and tertiary structures after incubation even in boiling water. This approach, outside the conventional environment for bioactivities of mesophilic proteins, provides a general strategy to dramatically increase the Tm (melting temperature) of mesophilic proteins without any changes to amino sequences of the native proteins. Current work offers a new insight with protein stability engineering for potential application, including vaccine storage and enzyme engineering., Graphical abstract, Highlights • Preserving bioactivities of proteins in hyperthermia water is promising. • Amphiphilic polymers could protect mesophilic proteins even in boiling water. • Mesophilic proteins protected by amphiphilic polymers show dramatically increased Tm. • The method offers application prospect for vaccine storage and enzyme engineering., Polymer chemistry ; Protein ; Bioengineering ; Biomaterials.