## 6 Discussions and Conclusions  
In this review, we reported advances in antibiotic delivery strategies based on polymer nanocarriers. A wide range of nano-platforms has been designed to overcome unfavorable physicochemical properties and the poor local bioavailability of several existing antibiotics, thereby ultimately improving their therapeutic features as well as slowing the emergence of drug resistance. Further, overcoming antibiotic resistance has also been accomplished by co-encapsulating therapeutic combinations in a single nanocarrier formulation, in which a synergistic antimicrobial effect has enhanced therapeutic efficacy. However, despite these promising preclinical results, several challenges remain for clinical exploitation of nanocarriers-based antibiotic delivery strategies. The safety of nanomaterials in the human body is among the major barriers to the clinical use of these dosage forms. Firstly, the safety of NPs depends on the administration route and their exposure (dose and duration) [141]. For instance, pulmonary administration minimizes systemic exposure to the nanocarrier formulation, thus bypassing the hepatic first-pass metabolism and increasing the delivery of the antibiotic cargo to the infected lung tissue. However, extensive exposure to nanomaterials through the lungs can induce excessive inflammatory responses and tissue necrosis [142]. For systemic administration, NPs can be distributed via the blood circulation to multiple organs, including the target site, and are simultaneously cleared by these organs [143]. Generally, during delivery of the antibiotic cargo, nanocarriers can simultaneously be metabolized (e.g., in the liver and spleen) or eliminated gradually (e.g., via renal filtration or biliary excretion) [144]. The fate of nanoparticles in the body depends on their physical and chemical properties, such as size, shape, and surface characteristics, which have been described in previous reviews [145; 146]. Through these parameters, the blood circulation half-life of NPs can be tunable to achieve favorable outcomes. For example, the long circulation time of nano-formulations in the bloodstream can be positively correlated with clinical effectiveness like enhanced nanocarrier deposition in the infected site (passive targeting) or bactericidal activities of time-dependent antibiotics. However, the prolonged circulatory residence time of the NPs can also relate to long-term toxicity and other side effects in the body [147]. Therefore, the balance between circulation time and in vivo clearance after treatment is critical in designing antibiotic-loaded nanocarriers. Although current animal models allow determining most of the pharmacokinetic profile of NPs to better understand their fate and behavior [143], several potential toxicities and long-term effects of nanomaterials may not be observed in preclinical trials. For instance, even where nanocarriers are derived from biodegradable polymers, the distribution and toxicity of their degradation products are challenging to determine experimentally [148]. Additionally, while the antimicrobial properties of nanomaterial and their degradation products on pathogenic bacteria are extensively reported, negative impacts on the human microbiota are not fully characterized. Therefore, a complete evaluation of both acute and long-term health risks of the polymer carrier materials (biopolymers and synthetic polymers) should be considered before designing novel drug delivery systems. In an ideal case, a nanocarrier formulation should degrade to uniform fragments that are considered of low toxicity and prone to rapid clearance out of the body. In addition, technical aspects and the risk-cost-benefit ratio also restrict the clinical implementation of nano-formulation [149]. The fact is that current efforts are mainly focused on developing antibiotic-delivery systems with a high degree of complexity (multimutional nanocarriers).