Traumatic spinal cord injury (SCI) is caused by external physical impacts and can induce complex cascade events, sometimes converging to paralysis. Existing clinical drugs to traumatic SCI have limited therapeutic efficacy because of either the poor blood–spinal cord barrier (BSCB) permeability or a single function. Here, we suggest a “pleiotropic messenger” strategy based on near-infrared (NIR)–triggered on-demand NO release at the lesion area for traumatic SCI recovery via the concurrent neuroregeneration and neuroprotection processing. This NO delivery system was constructed as upconversion nanoparticle (UCNP) core coated by zeolitic imidazolate framework–8 (ZIF-8) with NO donor (CysNO). This combined strategy substantial promotes the repair of SCI in vertebrates, ascribable to the pleiotropic effects of NO including the suppression of gliosis and inflammation, the promotion of neuroregeneration, and the protection of neurons from apoptosis, which opens intriguing perspectives not only in nerve repair but also in neurological research and tissue engineering.

Intracellular redox homeostasis and the iron metabolism system in tumor cells are closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite extensive attempts, maintaining high levels of intracellular catalysts (free iron) and reactants (H2O2) while decreasing the content of reactive oxygen species (ROS) scavengers (especially glutathione (GSH)) for enduring CDT still remains great challenges. Herein, SS bond‐rich dendritic mesoporous organic silica nanoparticles (DMON) are utilized as GSH‐depleting agents. After co‐loading Fe0 and a catalase inhibitor (3‐amino‐1,2,4‐triazole (AT)), a novel biodegradable nanocarrier is constructed as DMON@Fe0/AT. In the mildly acidic tumor microenvironment, on‐demand ferrous ions and AT are intelligently released. AT suppresses the activity of catalase for H2O2 hoarding, and the exposed DMON weakens ROS scavenging systems by persistently depleting intracellular GSH. The highly efficient •OH production by DMON@Fe0/AT can effectively attack mitochondria and downregulate the expression of ferroportin 1, which can disrupt the cellular iron metabolism system, leading to the desired retention of iron in the cytoplasm. More importantly, DMON@Fe0/AT exhibits a much more efficient CDT killing effect on 4T1 tumor cells than plain Fe0 nanoparticles, benefiting from their synergistic redox regulation and iron metabolism disruption. Overall, the as‐prepared intelligent, degradable DMON@Fe0/AT provides an innovative strategy for enduring CDT.

Developing smart photosensitizers that are sensitive to tumor-specific signals for minimal side effects and enhanced antitumor efficacy is a tremendous challenge for tumor phototherapies. Herein, we construct a nanoplatform with glutathione (GSH)-activatable and mitochondria-targeted pro-photosensitizer encapsulated by ultrasensitive pH-responsive polymer for achieving imaging-guided tumor-specific photodynamic therapy (PDT). The GSH-activatable pro-photosensitizer, di-cyanine (DCy7), has been synthesized where two cyanine moieties are covalently conjugated by a disulfide bond, and the hydrophobic DCy7 is further encapsulated with an amphiphilic pH-responsive diblock copolymer POEGMA-b-PDPA to form P@DCy7 nanoparticles. Upon endocytosis by cancer cells, P@DCy7 nanoparticles dissociate at endosome first and then DCy7 is released to cytoplasm and subsequently activated by the high concentration of GSH, finally targets mitochondria for organelle-targeted PDT. Moreover, intracellular antioxidant GSH is consumed during the activation procedure that is beneficial to efficient PDT. These P@DCy7 nanoparticles display selective phototoxicity against tumor cells (HepG2 or 4T1 cells) over normal cells (BEAS-2B cells) in vitro, and their GSH-activatable enhanced PDT efficacy is further confirmed in tumor-bearing mice. Thus, P@DCy7 nanoparticles allow for accurate and highly efficient PDT with minimal side effects, providing an attractive nanoplatform for organelle-targeted precise PDT.