Targeted delivery of nanomedicines to M2 tumorassociated macrophages (TAMs) has been proposed to reduce tumor promotion and enhance the efficacy of anticancer therapy. However, upregulated receptors on M2 TAMs are also expressed on M1 TAMs and other macrophages in normal tissues. Therefore, improving targeting specificity remains a key challenge. Here, we developed a precise M2 TAM-targeted delivery system using "eat-me" and "don't-eat-me" signals. A CD47-derived self-peptide ligand (don't-eat-me signal) and galactose ligand (eat-me signal) were introduced on liposomes. Cleavable phospholipid-polyethylene glycol was covered on the surface and could combine with the self-peptide to inhibit macrophage recognition even after immunoglobulin M adsorption and protect galactose from hepatic clearance to prolong the circulation time and promote the accumulation of liposomes in tumors. This detachable polymer can be removed by the redox microenvironment upon transcytosis through the tumor endothelium and re-expose the self-peptide and galactose. The self-peptide highly reduced M1 macrophage phagocytosis, and the galactose ligand enhanced the interaction between the liposomes and M2 macrophages. Thus, the modified liposomes enabled specific recognition of M1/M2 TAMs. In vitro evidence revealed reduced endocytosis of the liposomes by M1 macrophages. Moreover, in vivo studies demonstrated that doxorubicin-loaded liposomes efficiently eliminated M2 TAMs but did not affect M1 TAMs, enhancing the potency of the antitumor therapy. Collectively, our results demonstrate the potential of combining active escape and active targeting for precisely delivering a drug of interest to M2 macrophages and suggest its application in anticancer therapy.

Combination immunotherapy synergizing the PD-1 blockade with OX40 agonism has become a research hotspot, due to its enormous potential to overcome the restricted clinical objective response suffered by monotherapy. Questions of timing and sequence have been important aspects of immunotherapies when considering immunologic mechanisms; however, most of the time the straightforward additive approach was taken. Herein, our work is the first to investigate an alternative timing of aOX40 and aPD-1 treatment in melanoma-bearing mice, and it demonstrates that sequential administration (aOX40 first, then aPD-1 following) provided superior antitumor benefits than concurrent treatment. Based on that, to further avoid the limits suffered by solution forms, we adopted pharmaceutical technologies to construct an in situ-formed physical-and chemical-dually ROS-responsive nano-in-gel platform to implement sequential and prolonged release of aPD-1 and aOX40. Equipped with these advantages, the as-prepared (aPD-1NCs&aOX40)@Gels elicited augmented combination immunity and achieved great eradication of both primary and distant melanoma tumors in vivo.

With the rapid development of nanotechnology, carrier-based nano-drug delivery systems (DDSs) have been widely studied due to their advantages in optimizing pharmacokinetic and distribution profiles. However, despite those merits, some carrier-related limitations, such as low drug-loading capacity, systematic toxicity and unclear metabolism, usually prevent their further clinical transformation. Carrier-free nanomedicines with non-therapeutic excipients, are considered as an excellent paradigm to overcome these obstacles, owing to their superiority in improving both drug delivery efficacy and safety concern. In recent years, carrier-free nanomedicines have opened new horizons for cancer immunotherapy, and have already made outstanding progress. Herein, in this review, we are focusing on making an integrated and exhaustive overview of lately reports about them. Firstly, the major synthetic strategies of carrier-free nanomedicines are introduced, such as nanocrystals, prodrug-, amphiphilic drug-drug conjugates (ADDCs)-, polymer-drug conjugates-, and peptide-drug conjugates (PepDCs)-assembled nanomedicines. Afterwards, the typical applications of carrier-free nanomedicines in cancer immunotherapy are well-discussed, including cancer vaccines, cytokine therapy, enhancing T-cell checkpoint inhibition, as well as modulating tumor microenvironment (TME). After that, both the advantages and the potential challenges, as well as the future prospects of carrier-free nanomedicines in cancer immunotherapy, were discussed. And we believe that it would be of great potential practiced and reference value to the relative fields.

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