Inflammatory responses, manifested in excessive oxidative stress and microglia overactivation, together with metal ion-triggered amyloid-beta (Aβ) deposition, are critical hallmarks of Alzheimer’s disease (AD). The intricate pathogenesis causes severe impairment of neurons, which, in turn, exacerbates Aβ aggregation and facilitates AD progression. Herein, multifunctional melanin-like metal ion chelators and neuroinflammation regulators (named PDA@K) were constructed for targeted treatment of AD. In this platform, intrinsically bioactive material polydopamine nanoparticles (PDA) with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide, endowing the system with the capacity of enhanced pathological blood–brain barrier (BBB) crossing and lesion site accumulation via Aβ hitchhiking. In vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβ and were able to hitch a ride on Aβ to achieve increased pathological BBB crossing. The engineered PDA@K effectively mitigated Aβ aggregate and alleviated neuroinflammation. The modulated inflammatory microenvironment by PDA@K promoted microglial polarization toward the M2-like phenotype, which restored their critical functions for neuron care and plaque removal. After 3-week treatment of PDA@K, spatial learning and memory deficit as well as neurologic changes of FAD 4T transgenic mice were largely rescued. Transcriptomics analysis further revealed the therapeutic mechanism of PDA@K. Our study provided an appealing paradigm for directly utilizing intrinsic properties of nanomaterials as therapeutics for AD instead of just using them as nanocarriers, which largely widen the application of nanomaterials in AD therapy.

for overcoming the limitation facing traditional nanocarrier, but three stand out. Cyclodextrins come as a particular boon to hydrophobic chemodrugs, whose solubility can be notably improved by hostguest interaction. Another benefit arises from facile modification of such functional groups as targeting ligands, therapeutic or imaging agents into the building blocks. In addition, driven by dynamic and reversible host-guest recognition, these assemblies respond to a wide range of physiologic stimulus, like pH, redox, and enzyme, to on-demand release drug. This property further endows it with excellent biodegradability and rapid excretion, subsequently avoiding long-term retention toxicity. Despite these merits, the cyclodextrin-based nanoassembly is susceptible to ionic strength and protein adsorption during circulation, which might result in micelle collapse, burst drug release, and clearance. Therefore, enhancing structural robustness during circulation as well as on-demand disassembly at targeted sites is critical for the cyclodextrin-enabled drug delivery. Stimuli-responsive crosslinked strategies, [3][4][5] including the core or shell-crosslinked, represent a feasible candidate for enhancing stability under physiological environment and controllable drug release, relative to non-crosslinked counterparts. However, the incorporation of nonfunctional crosslinkers, such as disulfide, [6][7][8] salt bridge, [9] and Schiff base bonds, [10,11] will add to the complexity of preparation. On this ground, chosen crosslinkers with some specific antitumor features are seemingly more conducive to therapeutic response. Rosmarinic acid (RA), a natural phenolic compound, has two catechol moieties that can interact with boronic acid through pH-responsive boronate ester bonds, [3,[12][13][14] resulting in the formation of intraparticle crosslinkage, while inducing tumor apoptosis and suppressing the epithelial-mesenchymal transition (EMT) process of tumor cells. [15,16] RA with catechol structure also has strong antioxidant ability. [17] Concerning these superior features, introducing RA-boronic acid crosslinkage could equip cyclodextrinbased nanoassembly with multiple functions, including better stability, redox-mediating function, and antimetastasis ability. A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self-regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6-conjugated β-cyclodextrin (CD-Ce6) acts as the main PDT agent and ferrocene (Fc)-terminated phenylboronic acid-containing conjugates entering into the cavity of CD-Ce6, as well as rosmarinic acid (RA)boronic acid crosslinked shell. Compared with ...