Blood–brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB complicates the pharmacotherapy for CNS disorders as the most chemical drugs and biopharmaceuticals have been impeded to enter the brain. Insufficient drug delivery into the brain leads to low therapeutic efficacy as well as aggravated side effects due to the accumulation in other organs and tissues. Recent breakthrough in materials science and nanotechnology provides a library of advanced materials with customized structure and property serving as a powerful toolkit for targeted drug delivery. In-depth research in the field of anatomical and pathological study on brain and BBB further facilitates the development of brain-targeted strategies for enhanced BBB crossing. In this review, the physiological structure and different cells contributing to this barrier are summarized. Various emerging strategies for permeability regulation and BBB crossing including passive transcytosis, intranasal administration, ligands conjugation, membrane coating, stimuli-triggered BBB disruption, and other strategies to overcome BBB obstacle are highlighted. Versatile drug delivery systems ranging from organic, inorganic, and biologics-derived materials with their synthesis procedures and unique physio-chemical properties are summarized and analyzed. This review aims to provide an up-to-date and comprehensive guideline for researchers in diverse fields, offering perspectives on further development of brain-targeted drug delivery system.

The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG’s anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.

Ischemic stroke is lethal cerebrovascular disease, and reperfusion as the main strategy of blood supply restoration can cause severe ischemic brain damage. Considered as the major obstacle in medication for stroke, neuroinflammation after reperfusion undergoes dynamic progression, making precision treatment for stroke a Herculean task. In this work, we report a pathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke. Intrinsic free radical scavenging and tailored mesostructure of the nanosystem can attenuate oxidative stress at the initial stage. Upon microglial overactivation at the later stage, minocycline-loaded nanosystem can timely reverse the pro-inflammatory transition in response to activated matrix metalloproteinase-2, providing on-demand regulation. Further in vivo stroke study demonstrates a higher survival rate and improved brain recovery of the sequential strategy, compared with mono-therapy and combined therapy. Complemented with satisfactory biosafety results, this adaptive nanosystem for sequential and on-demand regulation of post-stroke neuroinflammation is a promising approach to ischemic stroke therapy.

Signal transducer and activator of transcription 3 (STAT3) is widely recognized as an attractive target for cancer therapy due to its significant role in the initiation and progression of tumorigenesis. However, existing STAT3 inhibitors have suffered from drawbacks including poor efficacy, limited specificity, and undesirable off-target effects, due to the challenging nature of identifying active sites or allosteric regulatory pockets on STAT3 amenable to small-molecule inhibition. In response to these obstacles, we utilize the innovative proteolysis targeting chimera (PROTAC) technology to create a highly specific decoy-targeted protein degradation system for STAT3 protein, termed D-PROTAC. This system fuses DNA decoy that targets STAT3 with an E3 ligase ligand, utilizing a click chemistry approach. Experimental results demonstrate that D-PROTAC efficiently mediates the degradation of the STAT3 protein across various cancer cell types, leading to the downregulation of crucial downstream STAT3 targets, inhibiting tumor cell growth, triggering cell cycle arrest and apoptosis, and suppressing tumor immune evasion. Furthermore, D-PROTAC is capable of achieving significant tumor suppression in xenograft models. Overall, our research validates that D-PROTAC can successfully target and eliminate the “undruggable” STAT3, showcasing specificity and potent antitumor effects. This strategy will suggest a promising avenue for the development of targeted therapies against the critical functions of STAT3 in human cancers and potentially other diseases.