Multidrug resistance (MDR) poses a great challenge to cancer therapy. It is difficult to inhibit the growth of MDR cancer due to its chemoresistance. Furthermore, MDR cancers are more likely to metastasize, causing a high mortality among cancer patients. In this study, a nanomedicine RGD-NPVs@MNPs/DOX was developed by encapsulating melanin nanoparticles (MNPs) and doxorubicin (DOX) inside RGD peptide (c(RGDyC))-modified nanoscale platelet vesicles (RGD-NPVs) to efficiently inhibit the growth and metastasis of drug-resistant tumors via a cancer cells and tumor vasculature dual-targeting strategy.Methods: The in vitro immune evasion potential and the targeting performance of RGD-NPVs@MNPs/DOX were examined using RAW264.7, HUVECs, MDA-MB-231 and MDA-MB-231/ADR cells lines. We also evaluated the pharmacokinetic behavior and the in vivo therapeutic performance of RGD-NPVs@MNPs/DOX using a MDA-MB-231/ADR tumor-bearing nude mouse model.Results: By taking advantage of the self-recognizing property of the platelet membrane and the conjugated RGD peptides, RGD-NPVs@MNPs/DOX was found to evade immune clearance and target the αvβ3 integrin on tumor vasculature and resistant breast tumor cells. Under irradiation with a NIR laser, RGD-NPVs@MNPs/DOX produced a multipronged effect, including reversal of cancer MDR, efficient killing of resistant cells by chemo-photothermal therapy, elimination of tumor vasculature for blocking metastasis, and long-lasting inhibition of the expressions of VEGF, MMP2 and MMP9 within the tumor.Conclusion: This versatile nanomedicine of RGD-NPVs@MNPs/DOX integrating unique biomimetic properties, excellent targeting performance, and comprehensive therapeutic strategies in one formulation might bring opportunities to MDR cancer therapy.

Nanomedicines are attractive paradigms to deliver drugs, contrast agents, immunomodulators, and gene editors for cancer therapy and diagnosis. However, the currently developed nanomedicine suffers from poor serum stability, premature drug release, and lack of responsiveness. Crosslinking strategy can be utilized to overcome these shortcomings by employing stimuli‐responsive chemical bonds to tightly hold the nanostructure and releasing the payloads spatiotemporally in a highly controlled manner. In this Review, we summarize the recently ingenious design of the stimuli‐responsive crosslinked nanomedicines (SCN) in the field of cancer treatment and their advances in circumventing the drawbacks of the conventional drug delivery system. We classify the SCNs into three categories based on the crosslinking strategies, including built‐in, on‐surface, and inter‐particle crosslinking nanomedicines. Thanks to the stimuli‐responsive crosslinkages, SCNs are capable of keeping robust stability during systemic circulation. They also respond to the particular tumoral conditions to experience a series of dynamic changes, such as the changes in size, surface charge, targeting moieties, integrity, and imaging signals. These characteristics allow them to efficiently overcome different biological barriers and substantially improve the drug delivery efficiency, tumor‐targeting ability, and imaging sensitivities. With the examples discussed, we envision that our perspectives can inspire more attempts to engineer intelligent nanomedicine to achieve effective cancer therapy and diagnosis.

The efficacy of therapeutics for brain tumors is seriously hampered by multiple barriers to drug delivery, including severe destabilizing effects in the blood circulation, the blood–brain barrier/blood–brain tumor barrier (BBB/BBTB), and limited tumor uptake. Here, a sequential targeting in crosslinking (STICK) nanodelivery strategy is presented to circumvent these important physiological barriers to improve drug delivery to brain tumors. STICK nanoparticles (STICK‐NPs) can sequentially target BBB/BBTB and brain tumor cells with surface maltobionic acid (MA) and 4‐carboxyphenylboronic acid (CBA), respectively, and simultaneously enhance nanoparticle stability with pH‐responsive crosslinkages formed by MA and CBA in situ. STICK‐NPs exhibit prolonged circulation time (17‐fold higher area under curve) than the free agent, allowing increased opportunities to transpass the BBB/BBTB via glucose‐transporter‐mediated transcytosis by MA. The tumor acidic environment then triggers the transformation of the STICK‐NPs into smaller nanoparticles and reveals a secondary CBA targeting moiety for deep tumor penetration and enhanced uptake in tumor cells. STICK‐NPs significantly inhibit tumor growth and prolong the survival time with limited toxicity in mice with aggressive and chemoresistant diffuse intrinsic pontine glioma. This formulation tackles multiple physiological barriers on‐demand with a simple and smart STICK design. Therefore, these features allow STICK‐NPs to unleash the potential of brain tumor therapeutics to improve their treatment efficacy.

Glioblastoma multiforme (GBM) is an aggressive and malignant brain tumor with high mortality. Current treatment strategies are still unsatisfactory on this devastating disease. Here, we developed a glucose-functionalized liposome (gLTP)...

Gadolinium-based contrast agents (GBCAs) are the most widely used T 1 contrast agents for magnetic resonance imaging (MRI) and have achieved remarkable success in clinical cancer diagnosis. However, GBCAs could cause severe nephrogenic systemic fibrosis to patients with renal insufficiency. Nevertheless, GBCAs are quickly excreted from the kidneys, which shortens their imaging window and prevents long-term monitoring of the disease per injection. Herein, a nephrotoxicity-free T 1 MRI contrast agent is developed by coordinating ferric iron into a telodendritic, micellar nanostructure. This new nano-enabled, iron-based contrast agent (nIBCA) not only can reduce the renal accumulation and relieve the kidney burden, but also exhibit a