Establishing a pre-metastatic niche (PMN) in secondary organs is a prerequisite for cancer metastases. Despite advances in cancer therapy, the efficient inhibition of PMN formation remains a clinical challenge. Recent advances in understanding the specific characteristics of PMN and advances in nanotechnology have provided hope for manipulating their microenvironments. A series of nanostrategies have been designed to eliminate the PMN, including the removal of pro-metastatic exosomes from the bloodstream for excretion via the intestines, the targeting and scavenging of myeloid-derived suppressor cells, fibroblasts, and critical extracellular matrix components, and the elimination of circulating tumor cells prior to colonization in distant organs. This review summarizes the underlying mechanisms of PMN formation, highlights the anti-PMN efficacy of currently reported nanostrategies, and underlines the unresolved questions.

Multidrug-resistance (MDR) featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic. Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR. However, the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites. In the present study, a type of self-targeting hyaluronate (HA) nanogels (^CDDPHANG/DOX) to reverse drug resistance through the synchronized pharmacokinetics, intratumoral distribution, and intracellular release of topoisomerase II inhibitor doxorubicin (DOX) and DNA- crosslinking agent cisplatin (CDDP) is developed. With prolonged circulation time and enhanced intratumoral accumulation in vivo, ^CDDPHANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity. Besides, fluorescence imaging of DOX combined with the micro-computed tomography (micro-CT) imaging of CDDP facilitates the visualization of this combination tumor chemotherapy. With visualizable synchronized drug delivery, the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.

Immunotherapy is a promising strategy to inhibit cancer progression via activation of the immune system. In immunotherapy, adjuvants as immunologic stimulants or delivery systems play a critical role in inducing the antitumor immune response and decreasing the side effects of immune stimulants. Polymer nanoparticles have attracted increasing attention as an indispensable component of immunotherapy, owing to their favorable properties, such as excellent biocompatibility and biodegradability, flexible size, high activity as immune stimulants, large surface area for binding multivalent immune ligands, and high loading capacity for immune-related components. In cancer immunotherapy, polymer nanoparticles can protect cargo from the surrounding milieu, deliver the antigens and immunostimulatory molecules to antigen-presenting cells, or stimulate robust T cell response. This review summarizes the current advancements in polymer nanoparticle adjuvants for cancer immunotherapy and predicts their prospects in fundamental and clinical studies.

Osteosarcoma is the most common malignancy in the bone. Current chemotherapy offers limited efficacy with significant side effects, especially for advanced and relapsed osteosarcomas. Nanoparticle-formulated chemotherapeutic drugs may be used to resolve these issues, but several aspects of these formulations remain unsatisfactory, such as how to improve their stability in the bloodstream, prevent undesirable drug leakage, and enhance targeted drug accumulation in the tumor. In this study, a tumor microenvironment-responsive calcium carbonate (CaCO₃)-crosslinked hyaluronate (HA) nanoparticle was prepared via a "green" process to effectively deliver doxorubicin (DOX) for the treatment of various stages of osteosarcoma. The DOX-loaded hyaluronate-calcium carbonate hybrid nanoparticle (HA-DOX/CaCO₃) demonstrated superior stability both in vitro and in vivo, and rapidly released DOX at the tumor site when triggered by the acidic tumor microenvironment. Compared with free DOX and a non-crosslinked nanoparticle (HA-DOX), HA-DOX/CaCO₃ exhibited the most potent inhibition efficacy toward both primary and advanced models of murine osteosarcoma, resulting in effective tumor inhibition, improved survival time, and reduced adverse effects. Most importantly, in the advanced osteosarcoma model, HA-DOX/CaCO₃ potently suppressed tumor growth by 84.6%, which indicates the potential of this platform for osteosarcoma treatment, particularly for advanced and relapsed cases. The proposed polysaccharide nanoparticle would be a promising drug delivery platform to advance osteosarcoma nanomedicine.