Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant

To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely.

To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely.

To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely.

To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely.

To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely.

To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely.