Anti-inflammatory therapy is often considered as an effective way to treat sepsis, but it only relives systemic inflammation without protecting the damaged vital organs. In our present study, we found that, lung is the most vulnerable organ compared to other vital organs in the progression of sepsis, characterized by excessively inflammatory response and activated platelet accumulation. Herein, an activated platelet-targted nanoparticle (P-TPNP-pD) was designed to facilitate drug delivery to sepsis-damaged lungs. Because of the high expression of P-selectin on activated platelets, P-TPNP-pD, modified with a P-selectin-targeting peptide (PTP), could target activated platelets and significantly accumulate in sepsis-damaged lungs via effective P-selectin-PTP binding. Meanwhile, due to the low pH of inflammation sites in sepsis-damaged lungs, nanoparticles with polydopamine (pD) modification could release anti-inflammatory drugs (Piceatannol, PIC) in a pH-responsive manner. However, the anti-inflammatory treatment was insufficient to alleviate lung injury in sepsis. Aggregation of activated platelets in the lungs induced by sepsis often leads to the formation of thrombosis, resulting in pulmonary dysfunction. Therefore, we further co-loaded anti-thrombotic drugs (Ticagrelor, TIC) into those nanoparticles. The dual anti-inflammatory/anti-thrombotic therapy could profoundly achieve lung protection in a sepsis mouse model with less infiltration of neutrophils and platelets, and reduce the risk of crosstalk between neutrophils and platelets simultaneously. This work provided proof-of-concept strategy to relive systemic inflammation and protect the vital organs of lung from inflammation and thrombosis in the progression of sepsis.

Oral delivery of protein and peptide drugs presents considerable challenges due to their susceptibility to digestive enzymes in gastrointestinal (GI) tract and low efficiency of transepithelial transport. Herein, inspired by efficient absorption of protein-based nutrients, we constructed several kinds of oral drug delivery systems by mimicking natural amino acid and oligopeptide absorption route. Three kinds of amino acids and two kinds of oligopeptides were chosen as targeting ligands to mediate transportation of orally administered nanoparticles (NPs). Liraglutide (Lira), a kind of glucagon like peptide-1 (GLP-1) receptor agonist, was used as model drug. These functionalized NPs could protect Lira from enzymatic degradation in GI tract. Moreover, compared with amino acid-modified NPs, oligopeptide-modified NPs exhibited greater transepithelial transport efficiency and were primarily absorbed in the proximal small intestine due to the high expression and transportation mediated by proton coupled oligopeptide transporter 1 (PEPT1). These Lira-loaded NPs could effectively control the blood glucose level, reduce plasma lipid level, and repair tissue damage on type 2 diabetic mice and even showed comparable hypoglycemic effects of subcutaneous injection (s.c.) free Lira. Our study demonstrates the potential of mimicking natural oligopeptide absorption route to enhance oral delivery of protein and peptide drugs.

The interaction between cancer cells and M2 tumor-associated macrophages (M2-TAMs) facilitates tumor growth and metastasis. However, cancer cells and M2-TAMs have different spatial distribution patterns, which requires distinct drug delivery strategies. Herein, based on different tumor-penetrating ability of nanocarriers, we developed a combinatory strategy that consists of a TAMs-targeting liposome (alanine-alanine-asparagine (AAN)-Lip-regorafenib (Rego)) and a cancer cells-targeting copolymer (internalizing RGD modified with N-(2-hydroxypropyl) methacrylamide-doxorubicin (iRGD-HD)). Our study confirmed AAN-Lip-Rego accumulated at perivascular sites where M2-TAM is located, while iRGD-HD penetrated into deep site of tumor to enter cancer cells. Thereafter, we found iRGD-HD induced cancer cells undergoing immunogenic cell death to enhance tumor infiltration of CD8⁺ T cells. Meanwhile, AAN-Lip-Rego efficiently repolarized TAMs from M2 into M1 to alleviate tumor immunosuppression, thus reviving CD8⁺ T cells. Moreover, the repolarization of TAMs led to dramatic downregulation of pro-metastatic factors expressed on cancer cells. As a result, such combinatory approach elicited robust antitumor immune responses and generated considerable anti-tumor and anti-metastasis efficacy to markedly inhibit primary tumor and spontaneous lung metastasis.

Mitochondria are highly involved in the metastasis of cancer cells. However, tumor cells impede the efficiency of mitochondrial targeted drugs by protecting mitochondria through an intrinsic and adaptive antioxidant mechanism. We aim to disturb the redox homeostasis by prolyl-isomerase PIN1 inhibitor all-trans retinoic acid (ATRA) to improve the therapeutic efficacy of mitochondrial targeted lonidamine (TL). The combination of ATRA and TL with a ratio of 2:1 was found to have the best synergistic effect in inhibiting the proliferation and metastasis of metastatic 4T1 breast cancer cells. Dual-drug loaded nanoparticles (TL-ATRA NPs) were further developed by self-assembly and were observed to disturb the redox homeostasis drastically and triggered a robust mitochondrial disruption on metastatic 4T1 breast cancer cells. The molecular mechanism was related to the downregulation of nuclear factor E2-related factor 2 (NRF2), a critical transcription factor that regulated antioxidant responses, and its downstream molecules. As a result, TL-ATRA NPs significantly suppressed the growth of primary tumors and the formation of lung metastasis nodes. Collectively, our findings showed that sensitizing mitochondria to anti-cancer drugs by disturbing redox homeostasis achieved a satisfactory therapeutic effect to inhibit tumor growth and metastasis.