Baojin Ma

Current periodontitis management is hindered by the inability to effectively reverse the dysbiotic microenvironment of persistent infection and restore immune homeostasis. Although photodynamic therapy (PDT) presents a promising non‐invasive antibacterial strategy, its clinical efficacy remains limited by poor microenvironmental selectivity and insufficient immunomodulatory capacity. Herein, we engineer a microenvironment‐responsive “trash‐to‐treasure” PDT strategy based on Bi ₂ O ₂ CO ₃ nanosheet‐assembled microspheres. This platform actively scavenges excess hydrogen sulfide (H ₂ S) within the periodontal pocket, triggering an in situ transformation into Bi ₂ O ₂ CO ₃ @Bi ₂ S ₃ heterojunctions. This H ₂ S‐triggered conversion neutralizes the pro‐inflammatory gasotransmitter and establishes an S‐scheme heterojunction with enhanced photocatalytic activity. The resulting reactive oxygen species (ROS)‐mediated oxidative stress, together with targeted disruption of bacterial iron metabolism, enables highly efficient photodynamic eradication of major periodontopathogens such as Porphyromonas gingivalis . Moreover, Bi ₂ O ₂ CO ₃ ‐mediated scavenging of pathological H ₂ S alleviates inflammatory responses in human gingival fibroblasts and reactivates macrophage respiratory burst for intracellular bacterial clearance. In vivo evaluations in a rat periodontitis model demonstrate effective inflammation resolution, suppression of alveolar bone loss, and robust tissue regeneration. This work introduces an intelligent therapeutic strategy that hijacks pathological H ₂ S as a photodynamic amplifier, establishing a microenvironment‐adaptive PDT paradigm for periodontal infection.

Neural stem cell (NSC) transplantation holds great potential for Alzheimer's disease (AD) therapy; however, its efficacy is severely compromised by the oxidative microenvironment, which impairs mitochondrial function and promotes aberrant glial differentiation. To overcome this barrier, lysosome‐responsive EGCG–lysine nanoparticles (EL NPs) were developed. Upon endo‐lysosomal disassembly, EL NPs release active components that scavenge reactive oxygen species (ROS) and restore mitochondrial bioenergetics via AMPK signaling. This metabolic rescue activates a Ca ^{2 +} ‐dependent MAPK pathway, driving commitment to the GABAergic neuronal lineage. Under oxidative stress, EL NPs enhanced neuronal differentiation efficiency by 2.5–3.0‐fold compared with spontaneous differentiation while suppressing astroglial activation. In an AD mouse model, transplantation of EL NP‐loaded NSCs promoted in situ neurogenesis, attenuated neuroinflammation, and restored cognitive performance to ∼89%–90% of wild‐type levels. These results present a translatable strategy to augment NSC‐based repair by modulating intracellular responses to oxidative stress and promoting neuronal differentiation.

Dental caries is driven by acidogenic biofilms embedded in an extracellular polymeric substance matrix, which shelters inner bacteria and diminishes antimicrobial efficacy. Nanozyme-based catalytic therapy is a promising alternative, whereas the inadequate catalytic performance coupled with weak interaction with bacteria severely limits the therapeutic efficacy. In this study, a pH-responsive polyethyleneimine-engineered cobalt sulfide (PCoS) nanozyme with a positive charge was developed, exhibiting enhanced oxidase- and peroxidase-like dual activities that were selectively initiated under acidic conditions. PCoS nanozyme effectively adsorbed onto bacterial surfaces, killed planktonic Streptococcus mutans , and disrupted mature biofilms by damaging bacterial membranes and reducing extracellular polymeric substance accumulation. Transcriptomic analysis further revealed alterations in metabolic pathways, suggesting that PCoS-mediated oxidative damage resulted in structural injury and bacterial physiology impairment. In a rat caries model, the dual enzyme–like activities of PCoS significantly reduced smooth and sulcal surface caries severity, preserved enamel structure by selectively suppressing cariogenic taxa, and maintained overall oral microbial diversity. These findings demonstrate that PCoS functions as a pH-responsive dual enzyme–like nanozyme that selectively disrupts cariogenic biofilms and prevents caries progression while preserving oral microbial homeostasis, supporting its potential for ecological caries management.

Innovations in therapeutic modalities and targeted drug delivery are two key approaches to improving the effectiveness of cancer treatment. With the development of therapeutic concepts and nanotechnology, recent research has shifted from tissue- or cell-level drug delivery to organelle-specific delivery to amplify therapeutic effects. Among these organelles, the endoplasmic reticulum (ER) has emerged as a particularly promising target because of its extensive membrane network, which serves as a major site for protein synthesis, lipid metabolism, calcium homeostasis, and intracellular signaling. The disruption of ER function can trigger severe cellular stress and apoptosis, providing a rationale for ER-targeted cancer therapy. However, traditional small-molecule drugs often exhibit poor ER specificity, rapid degradation, and limited intracellular accumulation, significantly restricting their therapeutic potential. In contrast, ER-targeting multifunctional nanoplatforms have demonstrated superior advantages, including enhanced stability, precise localization, controlled drug release, and multimodal therapeutic capabilities. In this Review, we systematically summarize the recent advances in ER-targeting nanotherapeutics and their applications in chemotherapy, phototherapy, immunotherapy, biotherapy, and combination therapy. Furthermore, we discuss the advantages, challenges, and mechanistic insights of these strategies, aiming to provide perspectives on accelerating the clinical translation of ER-targeting precision drugs.

Aging significantly impairs guided bone regeneration (GBR) by disrupting stem cell recruitment and exacerbating cellular senescence. To address this challenge, we engineered a quercetin and Sr-hydroxyapatite/poly(lactic-co-glycolic acid) (QSHP) Janus barrier membrane. The asymmetric design featured a dense poly(lactic-co-glycolic acid) layer for epithelial exclusion and a functionalized nanowire layer that enabled controlled codelivery of Sr ²⁺ and quercetin. In vitro, the QSHP membrane markedly enhanced the migration and proliferation of bone marrow mesenchymal stem cells while effectively mitigating H ₂ O ₂ -induced senescence and restoring osteogenic capacity. In aged rat mandibular defects, the QSHP membrane treatment yielded the highest newly formed bone volume and restored biomechanical properties approaching those of native bone. Histological and immunofluorescence analyses revealed accelerated early osteogenesis, increased recruitment of CD44 ⁺ stem cells, and concomitant attenuation of cellular senescence. Collectively, the QSHP membrane rejuvenates the senescence-impaired bone regenerative niche, enabling functional bone regeneration and offering a clinically promising strategy for GBR in aged patients.