Pyroptosis, systemic inflammation, and mitochondrial apoptosis are the three primary contributors to sepsis's multiple organ failure, the ultimate cause of high clinical mortality. Currently, the drugs under development only target a single pathogenesis, which is obviously insufficient. In this study, an acid‐responsive hollow mesoporous polydopamine (HMPDA) nanocarrier that is highly capable of carrying both the hydrophilic drug NAD ⁺ and the hydrophobic drug BAPTA‐AM, with its outer layer being sealed by the inflammatory targeting peptide PEG‐LSA, is developed. Once targeted to the region of inflammation, HMPDA begins depolymerization, releasing the drugs NAD ⁺ and BAPTA‐AM. Depletion of polydopamine on excessive reactive oxygen species production, promotion of ATP production and anti‐inflammation by NAD ⁺ replenishment, and chelation of BAPTA (generated by BA‐AM hydrolysis) on overloaded Ca ²⁺ can comprehensively block the three stages of sepsis, i.e., precisely inhibit the activation of pyroptosis pathway (NF‐ κ B‐NLRP3‐ASC‐Casp‐1), inflammation pathway (IL‐1 β , IL‐6, and TNF‐ α ), and mitochondrial apoptosis pathway (Bcl‐2/Bax‐Cyt‐C‐Casp‐9‐Casp‐3), thereby restoring intracellular homeostasis, saving the cells in a state of “critical survival,” further reducing LPS‐induced systemic inflammation, finally restoring the organ functions. In conclusion, the synthesis of this agent provides a simple and effective synergistic drug delivery nanosystem, which demonstrates significant therapeutic potential in a model of LPS‐induced sepsis.

Scalable manufacturing continues to present a major barrier for clinical translation of nanotherapeutics. Methods available for fabricating protein-encapsulating nanoparticles in a scalable fashion are scarce. Protein delivery often requires multiple functionalities to be incorporated into the same vehicle. Specifically for nanoparticle-mediated oral delivery of protein therapeutics, protection in GI tract, site-specific release, facilitating transmucosal permeation, and enhancing epithelial transport are a few desirable features to be engineered into a nanoparticle system. Here we devised a sequential flash nanocomplexation (FNC) technique for the scalable production of a core–shell structured nanoparticle system by combining materials choice and particle size and structure to fulfill these functions, therefore enhancing the delivery efficiency of insulin. This method is highly effective in controlling the size, generating core–shell structure with high encapsulation efficiency (97%) and payload capacity (67%) using insulin/L-penetratin complex nanoparticles as a core coated with hyaluronic acid (HA). Both the in vitro and in vivo models confirmed that the HA coating on these core–shell nanoparticles enhanced the permeation of nanoparticles through the intestinal mucus layer and improved trans-epithelial absorption of insulin nanoparticles; and the enhancement effect was most prominent using HA with the highest average molecular weight. The insulin-loaded nanoparticles were then encapsulated into enteric microcapsules (MCs) in an FNC process to provide additional protection against the acidic environment in the stomach while allowing rapid release of insulin nanoparticles when they reach small intestine. The optimized multifunctional MCs delivered an effective glucose reduction in a Type I diabetes rat model following a single oral administration, yielding a relative bioavailability of 11% in comparison with subcutaneous injection of free-form insulin. This FNC technique is highly effective in controlling particle size and structure to improve delivery properties and function. It can be easily extended to oral delivery for other protein therapeutics.

The dramatic increase of microbial resistances against conventional available antibiotics is a huge challenge to the effective treatment of infectious disease and thus becoming a daunting global threat of major concern, which necessitates the development of innovative therapeutics. Nanomaterial-based antimicrobial strategies have emerged as novel and promising tools to combat lethal bacteria and recalcitrant biofilm, featuring the abilities to evade existing drug resistance-related mechanisms. In this review, recent advances in “state-of-the-art” nanosystems which acting either as inherent therapeutics or nanocarriers for the precise delivery of antibiotics, are comprehensively summarized. Those nanosystems can effectively accumulate at the infectious sites, achieve multifunctional synergistic antibacterial efficacy, and provide controlled release of antibiotics in response to endogenous or exogenous stimulus (e.g., low pH, enzymes, or illumination). Especially, the nanoplatform that integrated with photothermal/photodynamic therapy (PTT/PDT) can enhance the bacterial destruction and biofilm penetration or ablation. In addition, nanoparticle-based approaches with enzymatically promoting bacterial killing, anti-virulence, and other mechanisms were also involved. Overall, this review provides crucial insights into the recent progress and remaining limitations of various antimicrobial nanotherapeutic strategies, and enlightens the further developments in this field simultaneously, which eventually benefiting public health.