Bone metastasis remains a clinical challenge and is still considered incurable. While nanoparticles-based drug delivery and photothermal therapy (PTT) show promise in treating subcutaneous solid tumor, their therapeutic outcome in treating bone metastasis is limited, due to the inaccessibility of bone metastatic site and the complexity of bone metastasis. Herein, we reported a simple nanoplatform composed of thermo-sensitive liposomes (TSL) and gold nanorods (GNR) to treat bone metastasis through improved chemotherapy combined with GNR-assisted PTT. Lipid combination of TSL was firstly tailored to regulate its stability under physiological condition as well as its sensitivity in responding to PTT-caused mild hyperthermia. The obtained TSL with loaded drug was then combined with GNR to form the nanoplatform through unsophisticated incubation. Cell experiments revealed that upon near-infrared (NIR) irradiation, the nanoplatform effectively inhibited the viability and migration ability of tumor cells through PTT, PTT-triggered thermo-sensitive drug release, and PTT-augmented sensitivity of tumor cells to drug. In a murine model of bone metastasis, the nanoplatform enabled effective delivery of loaded drug and GNR to bone metastatic site for rapid drug release upon local NIR irradiation. Through killing tumor cells and rebalancing the turnover of osteoclasts and osteoblasts, the nanoplatform largely preserved bone structure for pain relief and survival extension. Inspired by the simplicity of nanoplatform acquirement and treatment operation, the strategy of liposomes-based thermo-sensitive drug delivery in combination with GNR-assisted PTT is considered greatly promising in treating bone metastasis.

Clinical treatment of TNBC remains challenging, due to the lack of targeted therapies. As TNBC is highly hypoxic with higher HIF-1α expression than other subtypes, we fabricated hypoxia-responsive polymeric micelles co-loading drug and shRNA to treat TNBC by targeting hypoxic tumor microenvironment and subsequently targeting overexpressed HIF-1α under hypoxia. The micelles were assembled from methoxy-polyethylene glycol (mPEG) and poly-L-lysine (PLL) copolymer with AZO as a hypoxia-responsive bridge of mPEG and PLL. Once exposed to hypoxia, AZO bridge was cleaved, resulting in the disassembly of the micelles for rapid release. In vitro and in vivo results showed that the micelles enabled simultaneous delivery of drug and shRNA to hypoxic sites for site-specific rapid release, facilitated by sensitive response to hypoxia; hypoxia-responsive shRNA delivery effectively silenced HIF-1α and its downstream genes, which not only ameliorated the response of hypoxic tumor to drug, but also modulated tumor microenvironment for further improved drug and shRNA delivery; as a result, synergistic treatment of chemotherapy and HIF-1α targeted gene therapy inhibited the growth of primary TNBC tumor and its distant metastasis in a murine model of orthotopic TNBC. Together with their good biocompatibility, hypoxia-responsive polymeric micelles thus emerged as a safe, effective, and universally applicable drug and gene carrier for treatment of TNBC as well as other hypoxic tumors.

Neuropathic pain is a devastating experience for patients and its treatment remains challenging. Dorsal root ganglion (DRG) is currently an important therapeutic target and DRG-targeted analgesic delivery through systemic injection is however not reported. Herein, a disintegrin and metalloproteinase protein 8 (ADAM8), a membrane-anchored protein primarily recognized as a cancer biomarker, is found to be de novo and persistently upregulated in the DRG neurons in spared nerve injury (SNI) and chemotherapy-induced neuropathic pain (CINP), two neuropathic pain models with distinct mechanisms. We thus designed a DRG-targeted delivery strategy using lipid nanoparticles (LNPs), aiming to effectively deliver conventional analgesics to the DRG to improve analgesic effect through blocking pain signal transduction from the periphery to central nervous system. In vitro and in vivo results revealed that LNPs extended the duration of action of the free analgesic from less than 6 h to more than 24 h and particularly, showed therapeutic superiority over conventional liposomes, achieved by their good structural stability for a more sustained release kinetics. After functionalized with a specific ADAM8 inhibitory peptide, the intravenously injected LNPs facilitated analgesic accumulation in the DRG in SNI and CINP. As a result, the LNPs significantly improved the intensity of action for pain relief in a single or repeated treatments, which ultimately relieved pain-related psychiatric comorbidities, while not causing latent systemic toxicities. To our best knowledge, it is the first example of nanoparticles-based DRG-targeted delivery strategy through systemic injection in treating neuropathic pain.